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Inflammation in Health and Disease: New Insights and Therapeutic Avenues
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Inflammation in Health and Disease: New Insights and Therapeutic Avenues

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 140713

Special Issue Editors

Dr. Javier Conde Aranda

E-Mail Website
Guest Editor
Health Research Institute of Santiago de Compostela, Molecular and Cellular Gastroenterology, Santiago de Compostela, Spain
Interests: inflammation; autoimmune diseases; inflammatory bowel disease; colorectal cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Morena Scotece

E-Mail Website
Guest Editor
Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas and University of Salamanca, 37007 Salamanca, Spain
Interests: inflammation; fibrotic diseases; autoimmune diseases; rheumatology; drug discovery; natural molecules
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The inflammatory response is a highly evolved and complex process that allows the mobilization of leukocytes from circulation to injured tissues, where they remove pathogens and repair the tissue for its functional recovery. Under normal conditions, the inflammatory response is a self-limiting process that ends with the resolution of the inflammation and the restoration of tissue homeostasis. However, alterations in the mechanisms that regulate the promotion or the resolution of the inflammatory response cause the development of chronic inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, and diabetes. Moreover, it is well-described that inflammation is involved in the onset and progression of many other disorders not typically classified as autoimmune diseases, e.g., cancer, obesity, cardiovascular diseases, liver diseases, and fibrotic diseases. For that reason, the study and the understanding of the specific mechanisms that lead to aberrant inflammatory responses is crucial for the development of novel therapies for many different pathologies.

This Special Issue seeks basic and translational original and review articles focused on inflammation in health and disease. Potential topics include, but are not limited to, acute inflammation, chronic inflammation, resolution of inflammation, immunotherapy, and immune system regulation or infection.

Dr. Javier Conde Aranda
Dr. Morena Scotece
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • inflammation
  • inflammation resolution
  • autoimmune disease
  • cancer
  • immunotherapy
  • obesity
  • cardiovascular diseases
  • neurological disorders
  • respiratory diseases
  • liver diseases
  • fibrotic diseases

Published Papers (30 papers)

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Editorial

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5 pages, 210 KiB  
Editorial
Inflammation in Health and Disease: New Insights and Therapeutic Avenues
by Morena Scotece and Javier Conde-Aranda
Int. J. Mol. Sci. 2022, 23(15), 8392; https://doi.org/10.3390/ijms23158392 - 29 Jul 2022
Cited by 1 | Viewed by 1160
Abstract
The inflammatory response is an adaptive mechanism that evolved to fight against infections and tissue damage [...] Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)

Research

Jump to: Editorial, Review

16 pages, 3636 KiB  
Article
C3 Deficiency Leads to Increased Angiogenesis and Elevated Pro-Angiogenic Leukocyte Recruitment in Ischemic Muscle Tissue
by Philipp Götz, Anna Braumandl, Matthias Kübler, Konda Kumaraswami, Hellen Ishikawa-Ankerhold, Manuel Lasch and Elisabeth Deindl
Int. J. Mol. Sci. 2021, 22(11), 5800; https://doi.org/10.3390/ijms22115800 - 28 May 2021
Cited by 8 | Viewed by 3092
Abstract
The complement system is a potent inflammatory trigger, activator, and chemoattractant for leukocytes, which play a crucial role in promoting angiogenesis. However, little information is available about the influence of the complement system on angiogenesis in ischemic muscle tissue. To address this topic [...] Read more.
The complement system is a potent inflammatory trigger, activator, and chemoattractant for leukocytes, which play a crucial role in promoting angiogenesis. However, little information is available about the influence of the complement system on angiogenesis in ischemic muscle tissue. To address this topic and analyze the impact of the complement system on angiogenesis, we induced muscle ischemia in complement factor C3 deficient (C3−/−) and wildtype control mice by femoral artery ligation (FAL). At 24 h and 7 days after FAL, we isolated the ischemic gastrocnemius muscles and investigated them by means of (immuno-)histological analyses. C3−/− mice showed elevated ischemic damage 7 days after FAL, as evidenced by H&E staining. In addition, angiogenesis was increased in C3−/− mice, as demonstrated by increased capillary/muscle fiber ratio and increased proliferating endothelial cells (CD31+/BrdU+). Moreover, our results showed that the total number of leukocytes (CD45+) was increased in C3−/− mice, which was based on an increased number of neutrophils (MPO+), neutrophil extracellular trap formation (MPO+/CitH3+), and macrophages (CD68+) displaying a shift toward an anti-inflammatory and pro-angiogenic M2-like polarized phenotype (CD68+/MRC1+). In summary, we show that the deficiency of complement factor C3 increased neutrophil and M2-like polarized macrophage accumulation in ischemic muscle tissue, contributing to angiogenesis. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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17 pages, 2536 KiB  
Article
SUL-151 Decreases Airway Neutrophilia as a Prophylactic and Therapeutic Treatment in Mice after Cigarette Smoke Exposure
by Lei Wang, Charlotte E. Pelgrim, Daniël H. Swart, Guido Krenning, Adrianus C. van der Graaf, Aletta D. Kraneveld, Thea Leusink-Muis, Ingrid van Ark, Johan Garssen, Gert Folkerts and Saskia Braber
Int. J. Mol. Sci. 2021, 22(9), 4991; https://doi.org/10.3390/ijms22094991 - 8 May 2021
Cited by 8 | Viewed by 3099
Abstract
Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can [...] Read more.
Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 μg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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17 pages, 3263 KiB  
Article
Fibroinflammatory Signatures Increase with Age in the Human Ovary and Follicular Fluid
by Jordan H. Machlin, Seth J. Barishansky, John Kelsh, Megan J. Larmore, Brian W. Johnson, Michele T. Pritchard, Mary Ellen Pavone and Francesca E. Duncan
Int. J. Mol. Sci. 2021, 22(9), 4902; https://doi.org/10.3390/ijms22094902 - 5 May 2021
Cited by 16 | Viewed by 3160
Abstract
The female reproductive system ages before any other organ system in the body. This phenomenon can have tangible clinical implications leading to infertility, miscarriages, birth defects and systemic deterioration due to estrogen loss. “Fibroinflammation” is a hallmark of aging tissues; there is an [...] Read more.
The female reproductive system ages before any other organ system in the body. This phenomenon can have tangible clinical implications leading to infertility, miscarriages, birth defects and systemic deterioration due to estrogen loss. “Fibroinflammation” is a hallmark of aging tissues; there is an increase in inflammatory cytokines and fibrotic tissue in the aging ovarian stroma. We systematically evaluated immunomodulatory factors in human follicular fluid, which, like the stroma, is a critical ovarian microenvironment directly influencing the oocyte. Using a cytokine antibody array, we identified a unique fibroinflammatory cytokine signature in follicular fluid across an aging series of women (27.7–44.8 years). This signature (IL-3, IL-7, IL-15, TGFβ1, TGFβ3 and MIP-1) increased with chronologic age, was inversely correlated to anti-Müllerian hormone (AMH) levels, and was independent of body mass index (BMI). We focused on one specific protein, TGFβ3, for further validation. By investigating this cytokine in human cumulus cells and ovarian tissue, we found that the age-dependent increase in TGFβ3 expression was unique to the ovarian stroma but not other ovarian sub-compartments. This study broadens our understanding of inflammaging in the female reproductive system and provides a defined fibroinflammatory aging signature in follicular fluid and molecular targets in the ovary with potential clinical utility. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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19 pages, 4658 KiB  
Article
MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System
by Sarah Teuber-Hanselmann, Karl Worm, Nicole Macha and Andreas Junker
Int. J. Mol. Sci. 2021, 22(8), 3845; https://doi.org/10.3390/ijms22083845 - 8 Apr 2021
Cited by 8 | Viewed by 2349
Abstract
Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also [...] Read more.
Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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16 pages, 2416 KiB  
Article
Effects of a Novel GPR55 Antagonist on the Arachidonic Acid Cascade in LPS-Activated Primary Microglial Cells
by Soraya Wilke Saliba, Franziska Gläser, Anke Deckers, Albrecht Keil, Thomas Hurrle, Matthias Apweiler, Florian Ferver, Nicole Volz, Dominique Endres, Stefan Bräse and Bernd L. Fiebich
Int. J. Mol. Sci. 2021, 22(5), 2503; https://doi.org/10.3390/ijms22052503 - 2 Mar 2021
Cited by 12 | Viewed by 2963
Abstract
Neuroinflammation is a crucial process to maintain homeostasis in the central nervous system (CNS). However, chronic neuroinflammation is detrimental, and it is described in the pathogenesis of CNS disorders, including Alzheimer’s disease (AD) and depression. This process is characterized by the activation of [...] Read more.
Neuroinflammation is a crucial process to maintain homeostasis in the central nervous system (CNS). However, chronic neuroinflammation is detrimental, and it is described in the pathogenesis of CNS disorders, including Alzheimer’s disease (AD) and depression. This process is characterized by the activation of immune cells, mainly microglia. The role of the orphan G-protein-coupled receptor 55 (GPR55) in inflammation has been reported in different models. However, its role in neuroinflammation in respect to the arachidonic acid (AA) cascade in activated microglia is still lacking of comprehension. Therefore, we synthesized a novel GPR55 antagonist (KIT 10, 0.1–25 µM) and tested its effects on the AA cascade in lipopolysaccharide (LPS, 10 ng / mL)-treated primary rat microglia using Western blot and EIAs. We show here that KIT 10 potently prevented the release of prostaglandin E2 (PGE2), reduced microsomal PGE2 synthase (mPGES-1) and cyclooxygenase-2 (COX-2) synthesis, and inhibited the phosphorylation of Ikappa B-alpha (IκB-α), a crucial upstream step of the inflammation-related nuclear factor-kappaB (NF-κB) signaling pathway. However, no effects were observed on COX-1 and -2 activities and mitogen-activated kinases (MAPK). In summary, the novel GPR55 receptor antagonist KIT 10 reduces neuroinflammatory parameters in microglia by inhibiting the COX-2/PGE2 pathway. Further experiments are necessary to better elucidate its effects and mechanisms. Nevertheless, the modulation of inflammation by GPR55 might be a new therapeutic option to treat CNS disorders with a neuroinflammatory background such as AD or depression. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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15 pages, 26227 KiB  
Article
IL-6 Reduces Mitochondrial Replication, and IL-6 Receptors Reduce Chronic Inflammation in NAFLD and Type 2 Diabetes
by Daria Skuratovskaia, Aleksandra Komar, Maria Vulf, Hung Vu Quang, Egor Shunkin, Larisa Volkova, Natalia Gazatova, Pavel Zatolokin and Larisa Litvinova
Int. J. Mol. Sci. 2021, 22(4), 1774; https://doi.org/10.3390/ijms22041774 - 10 Feb 2021
Cited by 21 | Viewed by 2796
Abstract
Interleukin (IL)-6 family cytokines act through a receptor complex with gp130 subunits. IL-6 is a pleiotropic cytokine that regulates inflammation and liver regeneration. Mitochondria are the first to respond to stress and adapt their dynamics in conditions of damage. In this regard, the [...] Read more.
Interleukin (IL)-6 family cytokines act through a receptor complex with gp130 subunits. IL-6 is a pleiotropic cytokine that regulates inflammation and liver regeneration. Mitochondria are the first to respond to stress and adapt their dynamics in conditions of damage. In this regard, the study aimed to investigate the role of the IL-6 cytokine family (sIL-6Ra, gp130/sIL-6Rb, and IL-11) in the regulation of mitochondrial dynamics in the liver in obese patients and to assess the contribution of these cytokines to the pathogenesis of type 2 diabetes mellitus (T2DM). We studied 134 obese patients with and without T2DM and 41 healthy donors. We found that increasing the concentration of sIL-6Ra and gp130/sIL-6Rb protected against carbohydrate disorders in obese patients and prevented non-alcoholic fatty liver disease (NAFLD) progression in obese patients. An increase in plasma IL-6 levels is associated with decreased, mitochondrial transcription factor A (TFAM) protein production in liver biopsies in obese patients with and without T2DM. Replication, transcription, and division processes in liver biopsy were reduced in patients with T2DM. Inflammatory processes stimulate liver cell apoptosis in obese patients with T2DM. The increase in IL-11 levels is associated with decreased pro-apoptotic Bcl-2-associated X protein (BAX) protein production in obese patients with and without T2DM. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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23 pages, 7799 KiB  
Article
Dual Role of Interleukin-10 in Murine NZB/W F1 Lupus
by Anaïs Amend, Natalie Wickli, Anna-Lena Schäfer, Dalina T. L. Sprenger, Rudolf A. Manz, Reinhard E. Voll and Nina Chevalier
Int. J. Mol. Sci. 2021, 22(3), 1347; https://doi.org/10.3390/ijms22031347 - 29 Jan 2021
Cited by 14 | Viewed by 3819
Abstract
As a key anti-inflammatory cytokine, IL-10 is crucial in preventing inflammatory and autoimmune diseases. However, in human and murine lupus, its role remains controversial. Our aim was to understand regulation and immunologic effects of IL-10 on different immune functions in the setting of [...] Read more.
As a key anti-inflammatory cytokine, IL-10 is crucial in preventing inflammatory and autoimmune diseases. However, in human and murine lupus, its role remains controversial. Our aim was to understand regulation and immunologic effects of IL-10 on different immune functions in the setting of lupus. This was explored in lupus-prone NZB/W F1 mice in vitro and vivo to understand IL-10 effects on individual immune cells as well as in the complex in vivo setting. We found pleiotropic IL-10 expression that largely increased with progressing lupus, while IL-10 receptor (IL-10R) levels remained relatively stable. In vitro experiments revealed pro- and anti-inflammatory IL-10 effects. Particularly, IL-10 decreased pro-inflammatory cytokines and slowed B cell proliferation, thereby triggering plasma cell differentiation. The frequent co-expression of ICOS, IL-21 and cMAF suggests that IL-10-producing CD4 T cells are important B cell helpers in this context. In vitro and in vivo effects of IL-10 were not fully concordant. In vivo IL-10R blockade slightly accelerated clinical lupus manifestations and immune dysregulation. Altogether, our side-by-side in vitro and in vivo comparison of the influence of IL-10 on different aspects of immunity shows that IL-10 has dual effects. Our results further reveal that the overall outcome may depend on the interplay of different factors such as target cell, inflammatory and stimulatory microenvironment, disease model and state. A comprehensive understanding of such influences is important to exploit IL-10 as a therapeutic target. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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16 pages, 6739 KiB  
Article
Titanium Dioxide Presents a Different Profile in Dextran Sodium Sulphate-Induced Experimental Colitis in Mice Lacking the IBD Risk Gene Ptpn2 in Myeloid Cells
by Javier Conde, Marlene Schwarzfischer, Egle Katkeviciute, Janine Häfliger, Anna Niechcial, Nathalie Brillant, Roberto Manzini, Katharina Bäbler, Kirstin Atrott, Silvia Lang and Michael Scharl
Int. J. Mol. Sci. 2021, 22(2), 772; https://doi.org/10.3390/ijms22020772 - 14 Jan 2021
Cited by 3 | Viewed by 2094
Abstract
Environmental and genetic factors have been demonstrated to contribute to the development of inflammatory bowel disease (IBD). Recent studies suggested that the food additive; titanium dioxide (TiO2) might play a causative role in the disease. Therefore, in the present study we [...] Read more.
Environmental and genetic factors have been demonstrated to contribute to the development of inflammatory bowel disease (IBD). Recent studies suggested that the food additive; titanium dioxide (TiO2) might play a causative role in the disease. Therefore, in the present study we aimed to explore the interaction between the food additive TiO2 and the well-characterized IBD risk gene protein tyrosine phosphatase non-receptor type 2 (Ptpn2) and their role in the development of intestinal inflammation. Dextran sodium sulphate (DSS)-induced acute colitis was performed in mice lacking the expression of Ptpn2 in myeloid cells (Ptpn2LysMCre) or their wild type littermates (Ptpn2fl/fl) and exposed to the microparticle TiO2. The impact of Ptpn2 on TiO2 signalling pathways and TiO2-induced IL-1β and IL-10 levels were studied using bone marrow-derived macrophages (BMDMs). Ptpn2LysMCre exposed to TiO2 exhibited more severe intestinal inflammation than their wild type counterparts. This effect was likely due to the impact of TiO2 on the differentiation of intestinal macrophages, suppressing the number of anti-inflammatory macrophages in Ptpn2 deficient mice. Moreover, we also found that TiO2 was able to induce the secretion of IL-1β via mitogen-activated proteins kinases (MAPKs) and to repress the expression of IL-10 in bone marrow-derived macrophages via MAPK-independent pathways. This is the first evidence of the cooperation between the genetic risk factor Ptpn2 and the environmental factor TiO2 in the regulation of intestinal inflammation. The results presented here suggest that the ingestion of certain industrial compounds should be taken into account, especially in individuals with increased genetic risk Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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19 pages, 3572 KiB  
Article
Systemic Inflammation and the Breakdown of Intestinal Homeostasis Are Key Events in Chronic Spinal Cord Injury Patients
by David Diaz, Elisa Lopez-Dolado, Sergio Haro, Jorge Monserrat, Carlos Martinez-Alonso, Dimitrios Balomeros, Agustín Albillos and Melchor Alvarez-Mon
Int. J. Mol. Sci. 2021, 22(2), 744; https://doi.org/10.3390/ijms22020744 - 13 Jan 2021
Cited by 19 | Viewed by 2548
Abstract
Our aim was to investigate the subset distribution and function of circulating monocytes, proinflammatory cytokine levels, gut barrier damage, and bacterial translocation in chronic spinal cord injury (SCI) patients. Thus, 56 SCI patients and 28 healthy donors were studied. The levels of circulating [...] Read more.
Our aim was to investigate the subset distribution and function of circulating monocytes, proinflammatory cytokine levels, gut barrier damage, and bacterial translocation in chronic spinal cord injury (SCI) patients. Thus, 56 SCI patients and 28 healthy donors were studied. The levels of circulating CD14+highCD16−, CD14+highCD16+, and CD14+lowCD16+ monocytes, membrane TLR2, TLR4, and TLR9, phagocytic activity, ROS generation, and intracytoplasmic TNF-α, IL-1, IL-6, and IL-10 after lipopolysaccharide (LPS) stimulation were analyzed by polychromatic flow cytometry. Serum TNF-α, IL-1, IL-6 and IL-10 levels were measured by Luminex and LPS-binding protein (LBP), intestinal fatty acid-binding protein (I-FABP) and zonulin by ELISA. SCI patients had normal monocyte counts and subset distribution. CD14+highCD16− and CD14+highCD16+ monocytes exhibited decreased TLR4, normal TLR2 and increased TLR9 expression. CD14+highCD16− monocytes had increased LPS-induced TNF-α but normal IL-1, IL-6, and IL-10 production. Monocytes exhibited defective phagocytosis but normal ROS production. Patients had enhanced serum TNF-α and IL-6 levels, normal IL-1 and IL-10 levels, and increased circulating LBP, I-FABP, and zonulin levels. Chronic SCI patients displayed impaired circulating monocyte function. These patients exhibited a systemic proinflammatory state characterized by enhanced serum TNF-α and IL-6 levels. These patients also had increased bacterial translocation and gut barrier damage. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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17 pages, 4759 KiB  
Article
Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis
by Khai Gene Leong, Elyce Ozols, John Kanellis, Shawn S. Badal, John T. Liles, David J. Nikolic-Paterson and Frank Y. Ma
Int. J. Mol. Sci. 2021, 22(1), 271; https://doi.org/10.3390/ijms22010271 - 29 Dec 2020
Cited by 12 | Viewed by 2382
Abstract
Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, [...] Read more.
Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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12 pages, 1278 KiB  
Article
Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia
by Alessandra Di Paola, Giuseppe Palumbo, Pietro Merli, Maura Argenziano, Chiara Tortora, Luisa Strocchio, Domenico Roberti, Claudia Santoro, Silverio Perrotta and Francesca Rossi
Int. J. Mol. Sci. 2021, 22(1), 97; https://doi.org/10.3390/ijms22010097 - 24 Dec 2020
Cited by 23 | Viewed by 2754
Abstract
Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibodies-mediated platelet destruction, a prevalence of M1 pro-inflammatory macrophage phenotype and an elevated T helper 1 and T helper 2 lymphocytes (Th1/Th2) ratio, resulting in impairment of inflammatory profile and immune response. Macrophages are [...] Read more.
Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibodies-mediated platelet destruction, a prevalence of M1 pro-inflammatory macrophage phenotype and an elevated T helper 1 and T helper 2 lymphocytes (Th1/Th2) ratio, resulting in impairment of inflammatory profile and immune response. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated macrophages (M2). They have a key role in ITP, acting both as effector cells, phagocytizing platelets, and, as antigen presenting cells, stimulating auto-antibodies against platelets production. Eltrombopag (ELT) is a thrombopoietin receptor agonist licensed for chronic ITP to stimulate platelet production. Moreover, it improves T and B regulatory cells functions, suppresses T-cells activity, and inhibits monocytes activation. We analyzed the effect of ELT on macrophage phenotype polarization, proposing a new possible mechanism of action. We suggest it as a mediator of macrophage phenotype switch from the M1 pro-inflammatory type to the M2 anti-inflammatory one in paediatric patients with ITP, in order to reduce inflammatory state and restore the immune system function. Our results provide new insights into the therapy and the management of ITP, suggesting ELT also as immune-modulating drug. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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10 pages, 1596 KiB  
Article
Angiopoietin-2 Promotes Inflammatory Activation in Monocytes of Systemic Sclerosis Patients
by Tiago Carvalheiro, Ana P. Lopes, Maarten van der Kroef, Beatriz Malvar-Fernandez, Carlos Rafael-Vidal, Anneline C. Hinrichs, Nila H. Servaas, Femke Bonte-Mineur, Marc R. Kok, Lorenzo Beretta, Maili Zimmermann, Wioleta Marut, Jose M. Pego-Reigosa, Timothy R. D. J. Radstake and Samuel Garcia
Int. J. Mol. Sci. 2020, 21(24), 9544; https://doi.org/10.3390/ijms21249544 - 15 Dec 2020
Cited by 9 | Viewed by 3251
Abstract
Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 [...] Read more.
Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 levels were measured in serum and skin of healthy controls (HCs) and SSc patients by ELISA and array profiling, respectively. mRNA expression of ANG2 was analyzed in monocytes, dermal fibroblasts, and human pulmonary arterial endothelial cells (HPAECs) by quantitative PCR. Monocytes were stimulated with Ang-2, or with serum from SSc patients in the presence of a Tie2 inhibitor or an anti-Ang2 neutralizing antibody. Interleukin (IL)-6 and IL-8 production was analyzed by ELISA. Ang-2 levels were elevated in the serum and skin of SSc patients compared to HCs. Importantly, serum Ang-2 levels correlated with clinical disease parameters, such as skin involvement. Lipopolysaccharide (LPS) LPS, R848, and interferon alpha2a (IFN-α) stimulation up-regulated the mRNA expression of ANG2 in monocytes, dermal fibroblasts, and HPAECs. Finally, Ang-2 induced the production of IL-6 and IL-8 in monocytes of SSc patients, while the inhibition of Tie2 or the neutralization of Ang-2 reduced the production of both cytokines in HC monocytes stimulated with the serum of SSc patients. Therefore, Ang-2 induces inflammatory activation of SSc monocytes and neutralization of Ang-2 might be a promising therapeutic target in the treatment of SSc. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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17 pages, 2907 KiB  
Article
Inhibition of HDAC Enzymes Contributes to Differential Expression of Pro-Inflammatory Proteins in the TLR-4 Signaling Cascade
by Ulrike Weiss, Moritz Möller, Sayed Adham Husseini, Christine Manderscheid, Julia Häusler, Gerd Geisslinger and Ellen Niederberger
Int. J. Mol. Sci. 2020, 21(23), 8943; https://doi.org/10.3390/ijms21238943 - 25 Nov 2020
Cited by 20 | Viewed by 3002
Abstract
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined [...] Read more.
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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Review

Jump to: Editorial, Research

22 pages, 1271 KiB  
Review
Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review
by Raquel Cano, José L. Pérez, Lissé Angarita Dávila, Ángel Ortega, Yosselin Gómez, Nereida Josefina Valero-Cedeño, Heliana Parra, Alexander Manzano, Teresa Isabel Véliz Castro, María P. Díaz Albornoz, Gabriel Cano, Joselyn Rojas-Quintero, Maricarmen Chacín and Valmore Bermúdez
Int. J. Mol. Sci. 2021, 22(9), 4807; https://doi.org/10.3390/ijms22094807 - 1 May 2021
Cited by 49 | Viewed by 6422
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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18 pages, 1635 KiB  
Review
Impact of Obesity-Induced Inflammation on Cardiovascular Diseases (CVD)
by Gopi Battineni, Getu Gamo Sagaro, Nalini Chintalapudi, Francesco Amenta, Daniele Tomassoni and Seyed Khosrow Tayebati
Int. J. Mol. Sci. 2021, 22(9), 4798; https://doi.org/10.3390/ijms22094798 - 30 Apr 2021
Cited by 75 | Viewed by 7373
Abstract
Overweight and obesity are key risk factors of cardiovascular disease (CVD). Obesity is currently presented as a pro-inflammatory state with an expansion in the outflow of inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), alongside the expanded emission of leptin. [...] Read more.
Overweight and obesity are key risk factors of cardiovascular disease (CVD). Obesity is currently presented as a pro-inflammatory state with an expansion in the outflow of inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), alongside the expanded emission of leptin. The present review aimed to evaluate the relationship between obesity and inflammation and their impacts on the development of cardiovascular disease. A literature search was conducted by employing three academic databases, namely PubMed (Medline), Scopus (EMBASE), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). The search presented 786 items, and by inclusion and exclusion filterers, 59 works were considered for final review. The Newcastle–Ottawa Scale (NOS) method was adopted to conduct quality assessment; 19 papers were further selected based on the quality score. Obesity-related inflammation leads to a low-grade inflammatory state in organisms by upregulating pro-inflammatory markers and downregulating anti-inflammatory cytokines, thereby contributing to cardiovascular disease pathogenesis. Because of inflammatory and infectious symptoms, adipocytes appear to instigate articulation and discharge a few intense stage reactants and carriers of inflammation. Obesity and inflammatory markers are strongly associated, and are important factors in the development of CVD. Hence, weight management can help prevent cardiovascular risks and poor outcomes by inhibiting inflammatory mechanisms. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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25 pages, 1535 KiB  
Review
Hypoalbuminemia as Surrogate and Culprit of Infections
by Christian J. Wiedermann
Int. J. Mol. Sci. 2021, 22(9), 4496; https://doi.org/10.3390/ijms22094496 - 26 Apr 2021
Cited by 106 | Viewed by 10530
Abstract
Hypoalbuminemia is associated with the acquisition and severity of infectious diseases, and intact innate and adaptive immune responses depend on albumin. Albumin oxidation and breakdown affect interactions with bioactive lipid mediators that play important roles in antimicrobial defense and repair. There is bio-mechanistic [...] Read more.
Hypoalbuminemia is associated with the acquisition and severity of infectious diseases, and intact innate and adaptive immune responses depend on albumin. Albumin oxidation and breakdown affect interactions with bioactive lipid mediators that play important roles in antimicrobial defense and repair. There is bio-mechanistic plausibility for a causal link between hypoalbuminemia and increased risks of primary and secondary infections. Serum albumin levels have prognostic value for complications in viral, bacterial and fungal infections, and for infectious complications of non-infective chronic conditions. Hypoalbuminemia predicts the development of healthcare-associated infections, particularly with Clostridium difficile. In coronavirus disease 2019, hypoalbuminemia correlates with viral load and degree of acute lung injury and organ dysfunction. Non-oncotic properties of albumin affect the pharmacokinetics and pharmacodynamics of antimicrobials. Low serum albumin is associated with inadequate antimicrobial treatment. Infusion of human albumin solution (HAS) supplements endogenous albumin in patients with cirrhosis of the liver and effectively supported antimicrobial therapy in randomized controlled trials (RCTs). Evidence of the beneficial effects of HAS on infections in hypoalbuminemic patients without cirrhosis is largely observational. Prospective RCTs are underway and, if hypotheses are confirmed, could lead to changes in clinical practice for the management of hypoalbuminemic patients with infections or at risk of infectious complications. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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22 pages, 878 KiB  
Review
New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis
by Jana Adamcakova and Daniela Mokra
Int. J. Mol. Sci. 2021, 22(8), 4162; https://doi.org/10.3390/ijms22084162 - 17 Apr 2021
Cited by 62 | Viewed by 5819
Abstract
Inhalation of silica particles is an environmental and occupational cause of silicosis, a type of pneumoconiosis. Development of the lung silicosis is a unique process in which the vicious cycle of ingestion of inhaled silica particles by alveolar macrophages and their release triggers [...] Read more.
Inhalation of silica particles is an environmental and occupational cause of silicosis, a type of pneumoconiosis. Development of the lung silicosis is a unique process in which the vicious cycle of ingestion of inhaled silica particles by alveolar macrophages and their release triggers inflammation, generation of nodular lesions, and irreversible fibrosis. The pathophysiology of silicosis is complex, and interactions between the pathomechanisms have not been completely understood. However, elucidation of silica-induced inflammation cascades and inflammation-fibrosis relations has uncovered several novel possibilities of therapeutic targeting. This article reviews new information on the pathophysiology of silicosis and points out several promising treatment approaches targeting silicosis-related pathways. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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14 pages, 2620 KiB  
Review
Inflammatory Molecules Associated with Ultraviolet Radiation-Mediated Skin Aging
by Tuba M. Ansary, Md. Razib Hossain, Koji Kamiya, Mayumi Komine and Mamitaro Ohtsuki
Int. J. Mol. Sci. 2021, 22(8), 3974; https://doi.org/10.3390/ijms22083974 - 12 Apr 2021
Cited by 109 | Viewed by 11633
Abstract
Skin is the largest and most complex organ in the human body comprised of multiple layers with different types of cells. Different kinds of environmental stressors, for example, ultraviolet radiation (UVR), temperature, air pollutants, smoking, and diet, accelerate skin aging by stimulating inflammatory [...] Read more.
Skin is the largest and most complex organ in the human body comprised of multiple layers with different types of cells. Different kinds of environmental stressors, for example, ultraviolet radiation (UVR), temperature, air pollutants, smoking, and diet, accelerate skin aging by stimulating inflammatory molecules. Skin aging caused by UVR is characterized by loss of elasticity, fine lines, wrinkles, reduced epidermal and dermal components, increased epidermal permeability, delayed wound healing, and approximately 90% of skin aging. These external factors can cause aging through reactive oxygen species (ROS)-mediated inflammation, as well as aged skin is a source of circulatory inflammatory molecules which accelerate skin aging and cause aging-related diseases. This review article focuses on the inflammatory pathways associated with UVR-mediated skin aging. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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22 pages, 8233 KiB  
Review
Diversified Stimuli-Induced Inflammatory Pathways Cause Skin Pigmentation
by Md Razib Hossain, Tuba M. Ansary, Mayumi Komine and Mamitaro Ohtsuki
Int. J. Mol. Sci. 2021, 22(8), 3970; https://doi.org/10.3390/ijms22083970 - 12 Apr 2021
Cited by 35 | Viewed by 5484
Abstract
The production of melanin pigments by melanocytes and their quantity, quality, and distribution play a decisive role in determining human skin, eye, and hair color, and protect the skin from adverse effects of ultraviolet radiation (UVR) and oxidative stress from various environmental pollutants. [...] Read more.
The production of melanin pigments by melanocytes and their quantity, quality, and distribution play a decisive role in determining human skin, eye, and hair color, and protect the skin from adverse effects of ultraviolet radiation (UVR) and oxidative stress from various environmental pollutants. Melanocytes reside in the basal layer of the interfollicular epidermis and are compensated by melanocyte stem cells in the follicular bulge area. Various stimuli such as eczema, microbial infection, ultraviolet light exposure, mechanical injury, and aging provoke skin inflammation. These acute or chronic inflammatory responses cause inflammatory cytokine production from epidermal keratinocytes as well as dermal fibroblasts and other cells, which in turn stimulate melanocytes, often resulting in skin pigmentation. It is confirmed by some recent studies that several interleukins (ILs) and other inflammatory mediators modulate the proliferation and differentiation of human epidermal melanocytes and also promote or inhibit expression of melanogenesis-related gene expression directly or indirectly, thereby participating in regulation of skin pigmentation. Understanding of mechanisms of skin pigmentation due to inflammation helps to elucidate the relationship between inflammation and skin pigmentation regulation and can guide development of new therapeutic pathways for treating pigmented dermatosis. This review covers the mechanistic aspects of skin pigmentation caused by inflammation. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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23 pages, 4453 KiB  
Review
Potential of Nutraceutical Supplementation in the Modulation of White and Brown Fat Tissues in Obesity-Associated Disorders: Role of Inflammatory Signalling
by Federica Scarano, Micaela Gliozzi, Maria Caterina Zito, Lorenza Guarnieri, Cristina Carresi, Roberta Macrì, Saverio Nucera, Miriam Scicchitano, Francesca Bosco, Stefano Ruga, Anna Rita Coppoletta, Rocco Mollace, Jessica Maiuolo, Irene Bava, Antonio Cardamone, Monica Ragusa, Ernesto Palma, Vincenzo Musolino and Vincenzo Mollace
Int. J. Mol. Sci. 2021, 22(7), 3351; https://doi.org/10.3390/ijms22073351 - 25 Mar 2021
Cited by 12 | Viewed by 4163
Abstract
The high incidence of obesity is associated with an increasing risk of several chronic diseases such as cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Sustained obesity is characterized by a chronic and unsolved inflammation of adipose tissue, which leads [...] Read more.
The high incidence of obesity is associated with an increasing risk of several chronic diseases such as cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Sustained obesity is characterized by a chronic and unsolved inflammation of adipose tissue, which leads to a greater expression of proinflammatory adipokines, excessive lipid storage and adipogenesis. The purpose of this review is to clarify how inflammatory mediators act during adipose tissue dysfunction in the development of insulin resistance and all obesity-associated diseases. In particular, we focused our attention on the role of inflammatory signaling in brown adipose tissue (BAT) thermogenic activity and the browning of white adipose tissue (WAT), which represent a relevant component of adipose alterations during obesity. Furthermore, we reported the most recent evidence in the literature on nutraceutical supplementation in the management of the adipose inflammatory state, and in particular on their potential effect on common inflammatory mediators and pathways, responsible for WAT and BAT dysfunction. Although further research is needed to demonstrate that targeting pro-inflammatory mediators improves adipose tissue dysfunction and activates thermogenesis in BAT and WAT browning during obesity, polyphenols supplementation could represent an innovative therapeutic strategy to prevent progression of obesity and obesity-related metabolic diseases. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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17 pages, 1012 KiB  
Review
The Pathophysiology of Osteoporosis after Spinal Cord Injury
by Ramsha Shams, Kelsey P. Drasites, Vandana Zaman, Denise Matzelle, Donald C. Shields, Dena P. Garner, Christopher J. Sole, Azizul Haque and Narendra L. Banik
Int. J. Mol. Sci. 2021, 22(6), 3057; https://doi.org/10.3390/ijms22063057 - 17 Mar 2021
Cited by 17 | Viewed by 4958
Abstract
Spinal cord injury (SCI) affects approximately 300,000 people in the United States. Most individuals who sustain severe SCI also develop subsequent osteoporosis. However, beyond immobilization-related lack of long bone loading, multiple mechanisms of SCI-related bone density loss are incompletely understood. Recent findings suggest [...] Read more.
Spinal cord injury (SCI) affects approximately 300,000 people in the United States. Most individuals who sustain severe SCI also develop subsequent osteoporosis. However, beyond immobilization-related lack of long bone loading, multiple mechanisms of SCI-related bone density loss are incompletely understood. Recent findings suggest neuronal impairment and disability may lead to an upregulation of receptor activator of nuclear factor-κB ligand (RANKL), which promotes bone resorption. Disruption of Wnt signaling and dysregulation of RANKL may also contribute to the pathogenesis of SCI-related osteoporosis. Estrogenic effects may protect bones from resorption by decreasing the upregulation of RANKL. This review will discuss the current proposed physiological and cellular mechanisms explaining osteoporosis associated with SCI. In addition, we will discuss emerging pharmacological and physiological treatment strategies, including the promising effects of estrogen on cellular protection. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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18 pages, 1615 KiB  
Review
New Perspectives in the Study of Intestinal Inflammation: Focus on the Resolution of Inflammation
by Miguel Camba-Gómez, Oreste Gualillo and Javier Conde-Aranda
Int. J. Mol. Sci. 2021, 22(5), 2605; https://doi.org/10.3390/ijms22052605 - 5 Mar 2021
Cited by 12 | Viewed by 3107
Abstract
Inflammation is an essential physiological process that is directed to the protection of the organism against invading pathogens or tissue trauma. Most of the existing knowledge related to inflammation is focused on the factors and mechanisms that drive the induction phase of this [...] Read more.
Inflammation is an essential physiological process that is directed to the protection of the organism against invading pathogens or tissue trauma. Most of the existing knowledge related to inflammation is focused on the factors and mechanisms that drive the induction phase of this process. However, since the recognition that the resolution of the inflammation is an active and tightly regulated process, increasing evidence has shown the relevance of this process for the development of chronic inflammatory diseases, such as inflammatory bowel disease. For that reason, with this review, we aimed to summarize the most recent and interesting information related to the resolution process in the context of intestinal inflammation. We discussed the advances in the understanding of the pro-resolution at intestine level, as well as the new mediators with pro-resolutive actions that could be interesting from a therapeutic point of view. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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14 pages, 1454 KiB  
Review
Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging
by Nao Nagai, Yotaro Kudo, Daisuke Aki, Hayato Nakagawa and Koji Taniguchi
Int. J. Mol. Sci. 2021, 22(5), 2238; https://doi.org/10.3390/ijms22052238 - 24 Feb 2021
Cited by 13 | Viewed by 2810
Abstract
Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation [...] Read more.
Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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16 pages, 1001 KiB  
Review
Microglia and Neuroinflammation: What Place for P2RY12?
by Albert Gómez Morillas, Valérie C. Besson and Dominique Lerouet
Int. J. Mol. Sci. 2021, 22(4), 1636; https://doi.org/10.3390/ijms22041636 - 6 Feb 2021
Cited by 59 | Viewed by 9097
Abstract
Microglia are immune brain cells involved in neuroinflammation. They express a lot of proteins on their surface such as receptors that can be activated by mediators released in the microglial environment. Among these receptors, purinergic receptor expression could be modified depending on the [...] Read more.
Microglia are immune brain cells involved in neuroinflammation. They express a lot of proteins on their surface such as receptors that can be activated by mediators released in the microglial environment. Among these receptors, purinergic receptor expression could be modified depending on the activation status of microglia. In this review, we focus on P2Y receptors and more specifically on P2RY12 that is involved in microglial motility and migration, the first step of neuroinflammation process. We describe the purinergic receptor families, P2RY12 structure, expression and physiological functions. The pharmacological and genetic tools for studying this receptor are detailed thereafter. Last but not least, we report the contribution of microglial P2RY12 to neuroinflammation in acute and chronic brain pathologies in order to better understand P2RY12 microglial role. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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13 pages, 698 KiB  
Review
Calcineurin and Systemic Lupus Erythematosus: The Rationale for Using Calcineurin Inhibitors in the Treatment of Lupus Nephritis
by Carlos Rafael-Vidal, Irene Altabás, Nair Pérez, Coral Mourino Rodríguez, Jose M. Pego-Reigosa and Samuel Garcia
Int. J. Mol. Sci. 2021, 22(3), 1263; https://doi.org/10.3390/ijms22031263 - 27 Jan 2021
Cited by 16 | Viewed by 6584
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical presentations that can affect almost all organ systems. Lupus nephritis (LN) is a severe complication that affects approximately half of the systemic erythematosus lupus (SLE) patients, which significantly [...] Read more.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical presentations that can affect almost all organ systems. Lupus nephritis (LN) is a severe complication that affects approximately half of the systemic erythematosus lupus (SLE) patients, which significantly increases the morbidity and the mortality risk. LN is characterized by the accumulation of immune complexes, ultimately leading to renal failure. Aberrant activation of T cells plays a critical role in the pathogenesis of both SLE and LN and is involved in the production of inflammatory cytokines, the recruitment of inflammatory cells to the affected tissues and the co-stimulation of B cells. Calcineurin is a serine-threonine phosphatase that, as a consequence of the T cell hyperactivation, induces the production of inflammatory mediators. Moreover, calcineurin is also involved in the alterations of the podocyte phenotype, which contribute to proteinuria and kidney damage observed in LN patients. Therefore, calcineurin inhibitors have been postulated as a potential treatment strategy in LN, since they reduce T cell activation and promote podocyte cytoskeleton stabilization, both being key aspects in the development of LN. Here, we review the role of calcineurin in SLE and the latest findings about calcineurin inhibitors and their mechanisms of action in the treatment of LN. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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27 pages, 2617 KiB  
Review
Toll-Like Receptors in Acute Kidney Injury
by Cristina Vázquez-Carballo, Melania Guerrero-Hue, Cristina García-Caballero, Sandra Rayego-Mateos, Lucas Opazo-Ríos, José Luis Morgado-Pascual, Carmen Herencia-Bellido, Mercedes Vallejo-Mudarra, Isabel Cortegano, María Luisa Gaspar, Belén de Andrés, Jesús Egido and Juan Antonio Moreno
Int. J. Mol. Sci. 2021, 22(2), 816; https://doi.org/10.3390/ijms22020816 - 15 Jan 2021
Cited by 39 | Viewed by 6091
Abstract
Acute kidney injury (AKI) is an important health problem, affecting 13.3 million individuals/year. It is associated with increased mortality, mainly in low- and middle-income countries, where renal replacement therapy is limited. Moreover, survivors show adverse long-term outcomes, including increased risk of developing recurrent [...] Read more.
Acute kidney injury (AKI) is an important health problem, affecting 13.3 million individuals/year. It is associated with increased mortality, mainly in low- and middle-income countries, where renal replacement therapy is limited. Moreover, survivors show adverse long-term outcomes, including increased risk of developing recurrent AKI bouts, cardiovascular events, and chronic kidney disease. However, there are no specific treatments to decrease the adverse consequences of AKI. Epidemiological and preclinical studies show the pathological role of inflammation in AKI, not only at the acute phase but also in the progression to chronic kidney disease. Toll-like receptors (TLRs) are key regulators of the inflammatory response and have been associated to many cellular processes activated during AKI. For that reason, a number of anti-inflammatory agents targeting TLRs have been analyzed in preclinical studies to decrease renal damage during AKI. In this review, we updated recent knowledge about the role of TLRs, mainly TLR4, in the initiation and development of AKI as well as novel compounds targeting these molecules to diminish kidney injury associated to this pathological condition. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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35 pages, 1037 KiB  
Review
The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease
by Aleksander J. Nowak and Borna Relja
Int. J. Mol. Sci. 2020, 21(24), 9407; https://doi.org/10.3390/ijms21249407 - 10 Dec 2020
Cited by 48 | Viewed by 6052
Abstract
Ethanol misuse is frequently associated with a multitude of profound medical conditions, contributing to health-, individual- and social-related damage. A particularly dangerous threat from this classification is coined as alcoholic liver disease (ALD), a liver condition caused by prolonged alcohol overconsumption, involving several [...] Read more.
Ethanol misuse is frequently associated with a multitude of profound medical conditions, contributing to health-, individual- and social-related damage. A particularly dangerous threat from this classification is coined as alcoholic liver disease (ALD), a liver condition caused by prolonged alcohol overconsumption, involving several pathological stages induced by alcohol metabolic byproducts and sustained cellular intoxication. Molecular, pathological mechanisms of ALD principally root in the innate immunity system and are especially associated with enhanced functionality of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is an interesting and convoluted DNA transcription regulator, promoting both anti-inflammatory and pro-inflammatory gene expression. Thus, the abundancy of studies in recent years underlines the importance of NF-κB in inflammatory responses and the mechanistic stimulation of inner molecular motifs within the factor components. Hereby, in the following review, we would like to put emphasis on the correlation between the NF-κB inflammation signaling pathway and ALD progression. We will provide the reader with the current knowledge regarding the chronic and acute alcohol consumption patterns, the molecular mechanisms of ALD development, the involvement of the NF-κB pathway and its enzymatic regulators. Therefore, we review various experimental in vitro and in vivo studies regarding the research on ALD, including the recent active compound treatments and the genetic modification approach. Furthermore, our investigation covers a few human studies. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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16 pages, 1370 KiB  
Review
The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19
by Alessandro Bellis, Ciro Mauro, Emanuele Barbato, Bruno Trimarco and Carmine Morisco
Int. J. Mol. Sci. 2020, 21(22), 8612; https://doi.org/10.3390/ijms21228612 - 15 Nov 2020
Cited by 17 | Viewed by 4426
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger “cytokine storm” leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 [...] Read more.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger “cytokine storm” leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on “multi-targeted” therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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34 pages, 5399 KiB  
Review
Adipokines and Inflammation: Focus on Cardiovascular Diseases
by Sandra Feijóo-Bandín, Alana Aragón-Herrera, Sandra Moraña-Fernández, Laura Anido-Varela, Estefanía Tarazón, Esther Roselló-Lletí, Manuel Portolés, Isabel Moscoso, Oreste Gualillo, José Ramón González-Juanatey and Francisca Lago
Int. J. Mol. Sci. 2020, 21(20), 7711; https://doi.org/10.3390/ijms21207711 - 18 Oct 2020
Cited by 49 | Viewed by 4991
Abstract
It is well established that adipose tissue, apart from its energy storage function, acts as an endocrine organ that produces and secretes a number of bioactive substances, including hormones commonly known as adipokines. Obesity is a major risk factor for the development of [...] Read more.
It is well established that adipose tissue, apart from its energy storage function, acts as an endocrine organ that produces and secretes a number of bioactive substances, including hormones commonly known as adipokines. Obesity is a major risk factor for the development of cardiovascular diseases, mainly due to a low grade of inflammation and the excessive fat accumulation produced in this state. The adipose tissue dysfunction in obesity leads to an aberrant release of adipokines, some of them with direct cardiovascular and inflammatory regulatory functions. Inflammation is a common link between obesity and cardiovascular diseases, so this review will summarise the role of the main adipokines implicated in the regulation of the inflammatory processes occurring under the scenario of cardiovascular diseases. Full article
(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues)
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