Glucocorticoid-Induced Proteins Annexin A1 and GILZ in Inflammation

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cell Signaling".

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Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
Interests: GC-induced proteins; Signaling in inflammation; Resolution of inflammation; Pro-resolving mediators; Infectious diseases

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Department Experimental & Translational Medicine, Division of Medicine, University College London, London, UK
Interests: resolution of inflammation; resolution mediators; inflammatory disease models; lung infection and cancer; host-directed therapy

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ImmuPhar—Immunopharmacology Section Committee of International Union of Basic and Clinical Pharmacology (IUPHAR), Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Interests: inflammation; lung, influenza; pneumonia; resolution of inflammation; immunopharmacology
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Department of Medicine and Surgery, Section of Pharmacology, University of Perugia, 06156 Perugia, Italy
Interests: pharmacology; inflammation; glucocorticoids; adaptive immunity; stem cells

Topical Collection Information

Dear Colleagues,

Glucocorticoids (GCs) are endogenous hormones that are critical for organism homeostasis and adaptation to environmental conditions. Because of their anti-inflammatory actions, synthetic GCs are extensively used in clinical practice to treat several inflammatory conditions, representing the first successful use of an endogenous molecule for therapeutic purposes. However, long-term use is limited by the development of serious adverse effects, and administration is discouraged in infectious settings, as the immunosuppressive actions of GCs may favor pathogen propagation. Glucocorticoid-induced leucine zipper (GILZ) and Annexin A1 (AnxA1) are GC-induced proteins intrinsically involved with the anti-inflammatory functions of GCs without the associated adverse metabolic effects. Furthermore, there is a genuine interest in GC-induced proteins' ability to shift the amplification phase of inflammation towards the resolution yet helping the host to deal with a given infection. Understanding how endogenous points of control within the inflammatory pathways operate and identifying the consequences of the disruption of these circuits might guide the development of novel treatment approaches for chronic inflammation, autoimmune diseases, and infections. This Collection of Cells welcomes original articles and reviews covering the broad spectrum of processes in which GC-induced proteins are involved, both in health and disease.

Prof. Dr. Lirlândia Pires De Sousa
Dr. Michelle Sugimoto
Dr. Luciana Tavares
Dr. Stefano Bruscoli
Collection Editors

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Keywords

  • annexin A1
  • glucocorticoid-induced leucine zipper
  • mediators of inflammation and resolution
  • temporal expression and regulation of GC-induced proteins in sterile and infectious diseases
  • regulation of leukocyte trafficking
  • programmed cell death
  • efferocytosis
  • tissue regeneration
  • signaling pathways induced by GC-induced proteins

Published Papers (15 papers)

2023

Jump to: 2022, 2021

18 pages, 3288 KiB  
Article
Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs)
by Musetta Paglialunga, Sara Flamini, Raffaele Contini, Marta Febo, Erika Ricci, Simona Ronchetti, Oxana Bereshchenko, Graziella Migliorati, Carlo Riccardi and Stefano Bruscoli
Cells 2023, 12(18), 2294; https://doi.org/10.3390/cells12182294 - 16 Sep 2023
Cited by 1 | Viewed by 1418
Abstract
Glucocorticoids (GCs) are commonly used to treat autoimmune and inflammatory diseases, but their clinical effects and long-term use can lead to serious side effects. New drugs that can replace GCs are needed. Glucocorticoid-induced leucine zipper (GILZ) is induced by GCs and mediates many [...] Read more.
Glucocorticoids (GCs) are commonly used to treat autoimmune and inflammatory diseases, but their clinical effects and long-term use can lead to serious side effects. New drugs that can replace GCs are needed. Glucocorticoid-induced leucine zipper (GILZ) is induced by GCs and mediates many of their anti-inflammatory effects, such as inhibiting the pro-inflammatory molecule NF-κB. The GILZ C-terminal domain (PER region) is responsible for GILZ/p65NF-κB interaction and consequent inhibition of its transcriptional activity. A set of five short peptides spanning different parts of the PER region of GILZ protein was designed, and their anti-inflammatory activity was tested, both in vitro and in vivo. We tested the biological activity of GILZ peptides in human lymphocytic and monocytic cell lines to evaluate their inhibitory effect on the NF-κB-dependent expression of pro-inflammatory cytokines. Among the tested peptides, the peptide named PEP-1 demonstrated the highest efficacy in inhibiting cell activation in vitro. Subsequently, PEP-1 was further evaluated in two in vivo experimental colitis models (chemically induced by DNBS administration and spontaneous colitis induced in IL-10 knock-out (KO) mice (to assess its effectiveness in counteracting inflammation. Results show that PEP-1 reduced disease severity in both colitis models associated with reduced NF-κB pro-inflammatory activity in colon lamina propria lymphocytes. This study explored GILZ-based ‘small peptides’ potential efficacy in decreasing lymphocyte activation and inflammation associated with experimental inflammatory bowel diseases (IBDs). Small peptides have several advantages over the entire protein, including higher selectivity, better stability, and bioavailability profile, and are easy to synthesize and cost-effective. Thus, identifying active GILZ peptides could represent a new class of drugs for treating IBD patients. Full article
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20 pages, 3245 KiB  
Article
GILZ Modulates the Recruitment of Monocytes/Macrophages Endowed with a Resolving Phenotype and Favors Resolution of Escherichia coli Infection
by Laís C. Grossi, Isabella Zaidan, Jéssica Amanda Marques Souza, Antônio Felipe S. Carvalho, Rodrigo C. O. Sanches, Camila Cardoso, Edvaldo S. Lara, Ana Clara M. Montuori-Andrade, Stefano Bruscoli, Maria Cristina Marchetti, Carlo Riccardi, Mauro M. Teixeira, Luciana P. Tavares, Juliana P. Vago and Lirlândia P. Sousa
Cells 2023, 12(10), 1403; https://doi.org/10.3390/cells12101403 - 17 May 2023
Cited by 1 | Viewed by 1532
Abstract
Macrophages are important effectors of inflammation resolution that contribute to the elimination of pathogens and apoptotic cells and restoration of homeostasis. Pre-clinical studies have evidenced the anti-inflammatory and pro-resolving actions of GILZ (glucocorticoid-induced leucine zipper). Here, we evaluated the role of GILZ on [...] Read more.
Macrophages are important effectors of inflammation resolution that contribute to the elimination of pathogens and apoptotic cells and restoration of homeostasis. Pre-clinical studies have evidenced the anti-inflammatory and pro-resolving actions of GILZ (glucocorticoid-induced leucine zipper). Here, we evaluated the role of GILZ on the migration of mononuclear cells under nonphlogistic conditions and Escherichia coli-evoked peritonitis. TAT-GILZ (a cell-permeable GILZ-fusion protein) injection into the pleural cavity of mice induced monocyte/macrophage influx alongside increased CCL2, IL-10 and TGF-β levels. TAT-GILZ-recruited macrophages showed a regulatory phenotype, exhibiting increased expression of CD206 and YM1. During the resolving phase of E. coli-induced peritonitis, marked by an increased recruitment of mononuclear cells, lower numbers of these cells and CCL2 levels were found in the peritoneal cavity of GILZ-deficient mice (GILZ−/−) when compared to WT. In addition, GILZ−/− showed higher bacterial loads, lower apoptosis/efferocytosis counts and a lower number of macrophages with pro-resolving phenotypes. TAT-GILZ accelerated resolution of E. coli-evoked neutrophilic inflammation, which was associated with increased peritoneal numbers of monocytes/macrophages, enhanced apoptosis/efferocytosis counts and bacterial clearance through phagocytosis. Taken together, we provided evidence that GILZ modulates macrophage migration with a regulatory phenotype, inducing bacterial clearance and accelerating the resolution of peritonitis induced by E. coli. Full article
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19 pages, 1420 KiB  
Review
The Multifaceted Role of Annexin A1 in Viral Infections
by Filipe Resende, Simone de Araújo, Luciana Pádua Tavares, Mauro Martins Teixeira and Vivian Vasconcelos Costa
Cells 2023, 12(8), 1131; https://doi.org/10.3390/cells12081131 - 11 Apr 2023
Cited by 1 | Viewed by 1942
Abstract
Dysregulated inflammatory responses are often correlated with disease severity during viral infections. Annexin A1 (AnxA1) is an endogenous pro-resolving protein that timely regulates inflammation by activating signaling pathways that culminate with the termination of response, clearance of pathogen and restoration of tissue homeostasis. [...] Read more.
Dysregulated inflammatory responses are often correlated with disease severity during viral infections. Annexin A1 (AnxA1) is an endogenous pro-resolving protein that timely regulates inflammation by activating signaling pathways that culminate with the termination of response, clearance of pathogen and restoration of tissue homeostasis. Harnessing the pro-resolution actions of AnxA1 holds promise as a therapeutic strategy to control the severity of the clinical presentation of viral infections. In contrast, AnxA1 signaling might also be hijacked by viruses to promote pathogen survival and replication. Therefore, the role of AnxA1 during viral infections is complex and dynamic. In this review, we provide an in-depth view of the role of AnxA1 during viral infections, from pre-clinical to clinical studies. In addition, this review discusses the therapeutic potential for AnxA1 and AnxA1 mimetics in treating viral infections. Full article
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19 pages, 12578 KiB  
Article
Role of Annexin A1 Secreted by Neutrophils in Melanoma Metastasis
by Silvana Sandri, Cristina Bichels Hebeda, Milena Fronza Broering, Marina de Paula Silva, Luciana Facure Moredo, Milton José de Barros e Silva, André Sapata Molina, Clóvis Antônio Lopes Pinto, João Pedreira Duprat Neto, Chris P. Reutelingsperger, Cristiane Damas Gil and Sandra Helena Poliselli Farsky
Cells 2023, 12(3), 425; https://doi.org/10.3390/cells12030425 - 27 Jan 2023
Cited by 2 | Viewed by 2391
Abstract
Annexin A1 (AnxA1) is highly secreted by neutrophils and binds to formyl peptide receptors (FPRs) to trigger anti-inflammatory effects and efferocytosis. AnxA1 is also expressed in the tumor microenvironment, being mainly attributed to cancer cells. As recruited neutrophils are player cells at the [...] Read more.
Annexin A1 (AnxA1) is highly secreted by neutrophils and binds to formyl peptide receptors (FPRs) to trigger anti-inflammatory effects and efferocytosis. AnxA1 is also expressed in the tumor microenvironment, being mainly attributed to cancer cells. As recruited neutrophils are player cells at the tumor sites, the role of neutrophil-derived AnxA1 in lung melanoma metastasis was investigated here. Melanoma cells and neutrophils expressing AnxA1 were detected in biopsies from primary melanoma patients, which also presented higher levels of serum AnxA1 and augmented neutrophil–lymphocyte ratio (NLR) in the blood. Lung melanoma metastatic mice (C57BL/6; i.v. injected B16F10 cells) showed neutrophilia, elevated AnxA1 serum levels, and higher labeling for AnxA1 in neutrophils than in tumor cells at the lungs with metastasis. Peritoneal neutrophils collected from naïve mice were co-cultured with B16F10 cells or employed to obtain neutrophil-conditioned medium (NCM; 18 h incubation). B16F10 cells co-cultured with neutrophils or with NCM presented higher invasion, which was abolished if B16F10 cells were previously incubated with FPR antagonists or co-cultured with AnxA1 knockout (AnxA1-/-) neutrophils. The depletion of peripheral neutrophils during lung melanoma metastasis development (anti-Gr1; i.p. every 48 h for 21 days) reduced the number of metastases and AnxA1 serum levels in mice. Our findings show that AnxA1 secreted by neutrophils favors melanoma metastasis evolution via FPR pathways, addressing AnxA1 as a potential biomarker for the detection or progression of melanoma. Full article
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2022

Jump to: 2023, 2021

19 pages, 2989 KiB  
Article
Annexin A1-FPR2/ALX Signaling Axis Regulates Acute Inflammation during Chikungunya Virus Infection
by Simone de Araújo, Victor R. de Melo Costa, Franciele M. Santos, Carla D. Ferreira de Sousa, Thaiane P. Moreira, Matheus R. Gonçalves, Franciel B. Félix, Celso M. Queiroz-Junior, Gabriel H. Campolina-Silva, Maurício Lacerda Nogueira, Michelle A. Sugimoto, Caio S. Bonilha, Mauro Perretti, Danielle G. Souza, Vivian V. Costa and Mauro M. Teixeira
Cells 2022, 11(17), 2717; https://doi.org/10.3390/cells11172717 - 31 Aug 2022
Cited by 5 | Viewed by 2409
Abstract
Chikungunya (CHIKV) is an arthritogenic alphavirus that causes a self-limiting disease usually accompanied by joint pain and/or polyarthralgia with disabling characteristics. Immune responses developed during the acute phase of CHIKV infection determine the rate of disease progression and resolution. Annexin A1 (AnxA1 [...] Read more.
Chikungunya (CHIKV) is an arthritogenic alphavirus that causes a self-limiting disease usually accompanied by joint pain and/or polyarthralgia with disabling characteristics. Immune responses developed during the acute phase of CHIKV infection determine the rate of disease progression and resolution. Annexin A1 (AnxA1) is involved in both initiating inflammation and preventing over-response, being essential for a balanced end of inflammation. In this study, we investigated the role of the AnxA1-FPR2/ALX pathway during CHIKV infection. Genetic deletion of AnxA1 or its receptor enhanced inflammatory responses driven by CHIKV. These knockout mice showed increased neutrophil accumulation and augmented tissue damage at the site of infection compared with control mice. Conversely, treatment of wild-type animals with the AnxA1 mimetic peptide (Ac2–26) reduced neutrophil accumulation, decreased local concentration of inflammatory mediators and diminished mechanical hypernociception and paw edema induced by CHIKV-infection. Alterations in viral load were mild both in genetic deletion or with treatment. Combined, our data suggest that the AnxA1-FPR2/ALX pathway is a potential therapeutic strategy to control CHIKV-induced acute inflammation and polyarthralgia. Full article
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13 pages, 2879 KiB  
Article
Expression Profiles of GILZ and Annexin A1 in Human Oral Candidiasis and Lichen Planus
by Mahmood S. Mozaffari and Rafik Abdelsayed
Cells 2022, 11(9), 1470; https://doi.org/10.3390/cells11091470 - 27 Apr 2022
Cited by 1 | Viewed by 3015
Abstract
Adrenal glands are the major source of glucocorticoids, but recent studies indicate tissue-specific production of cortisol, including that in the oral mucosa. Both endogenous and exogenous glucocorticoids regulate the production of several proteins, including the glucocorticoid-induced leucine zipper (GILZ) and Annexin A1, which [...] Read more.
Adrenal glands are the major source of glucocorticoids, but recent studies indicate tissue-specific production of cortisol, including that in the oral mucosa. Both endogenous and exogenous glucocorticoids regulate the production of several proteins, including the glucocorticoid-induced leucine zipper (GILZ) and Annexin A1, which play important roles in the regulation of immune and inflammatory responses. Common inflammation-associated oral conditions include lichen planus and candidiasis, but the status of GILZ and Annexin A1 in these human conditions remains to be established. Accordingly, archived paraffin-embedded biopsy samples were subjected to immunohistochemistry to establish tissue localization and profile of GILZ and Annexin A1 coupled with the use of hematoxylin–eosin stain for histopathological assessment; for comparison, fibroma specimens served as controls. Histopathological examination confirmed the presence of spores and pseudohyphae for oral candidiasis (OC) specimens and marked inflammatory cell infiltrates for both OC and oral lichen planus (OLP) specimens compared to control specimens. All specimens displayed consistent and prominent nuclear staining for GILZ throughout the full thickness of the epithelium and, to varying extent, for inflammatory infiltrates and stromal cells. On the other hand, a heterogeneous pattern of nuclear, cytoplasmic, and cell membrane staining was observed for Annexin A1 for all specimens in the suprabasal layers of epithelium and, to varying extent, for inflammatory and stromal cells. Semi-quantitative analyses indicated generally similar fractional areas of staining for both GILZ and Annexin A1 among the groups, but normalized staining for GILZ, but not Annexin A1, was reduced for OC and OLP compared to the control specimens. Thus, while the cellular expression pattern of GILZ and Annexin A1 does not differentiate among these conditions, differential cellular profiles for GILZ vs. Annexin A1 are suggestive of their distinct physiological functions in the oral mucosa. Full article
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13 pages, 3704 KiB  
Article
Annexin-A1-Derived Peptide Ac2-26 Suppresses Allergic Airway Inflammation and Remodelling in Mice
by Tatiana Paula Teixeira Ferreira, Fernanda Verdini Guimarães, Yago Amigo Pinho Jannini Sá, Natalia Barreto da Silva Ribeiro, Ana Carolina Santos de Arantes, Vinicius de Frias Carvalho, Lirlândia Pires Sousa, Mauro Perretti, Marco Aurélio Martins and Patrícia Machado Rodrigues e Silva
Cells 2022, 11(5), 759; https://doi.org/10.3390/cells11050759 - 22 Feb 2022
Cited by 6 | Viewed by 2278
Abstract
Annexin-A1 (AnxA1) and its N-terminal derived peptide Ac2-26 regulate the inflammatory response in several experimental models of disorders. This study evaluated the effect of endogenous AnxA1 and its N-terminal peptide Acetyl 2-26 (Ac2-26) on allergic asthma triggered by house dust mite (HDM) extract [...] Read more.
Annexin-A1 (AnxA1) and its N-terminal derived peptide Ac2-26 regulate the inflammatory response in several experimental models of disorders. This study evaluated the effect of endogenous AnxA1 and its N-terminal peptide Acetyl 2-26 (Ac2-26) on allergic asthma triggered by house dust mite (HDM) extract in mice. ANXA1−/− and wildtype (WT) mice were exposed to intranasal instillation of HDM every other day for 3 weeks, with analyses performed 24 h following the last exposure. Intranasal administration of peptide Ac2-26 was performed 1 h before HDM, beginning 1 week after the initial antigen application. ANXA1−/− mice stimulated with HDM showed marked exacerbations of airway hyperreactivity (AHR), eosinophil accumulation, subepithelial fibrosis, and mucus hypersecretion, all parameters correlating with overexpression of cytokines (IL-4, IL-13, TNF-α, and TGF-β) and chemokines (CCL11/eotaxin-1 and CCL2/MCP-1). Intranasal treatment with peptide Ac2-26 decreased eosinophil infiltration, peribronchiolar fibrosis, and mucus exacerbation caused by the allergen challenge. Ac2-26 also inhibited AHR and mediator production. Collectively, our findings show that the AnxA1-derived peptide Ac2-26 protects against several pathological changes associated with HDM allergic reaction, suggesting that this peptide or related AnxA1-mimetic Ac2-26 may represent promising therapeutic candidates for the treatment of allergic asthma. Full article
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19 pages, 3990 KiB  
Article
Glucocorticoid-Induced Leucine Zipper Alleviates Lung Inflammation and Enhances Bacterial Clearance during Pneumococcal Pneumonia
by Jéssica Amanda Marques Souza, Antônio Felipe S. Carvalho, Lais C. Grossi, Isabella Zaidan, Leonardo Camilo de Oliveira, Juliana P. Vago, Camila Cardoso, Marina G. Machado, Geovanna V. Santos Souza, Celso Martins Queiroz-Junior, Eric F. Morand, Stefano Bruscoli, Carlo Riccardi, Mauro M. Teixeira, Luciana P. Tavares and Lirlândia P. Sousa
Cells 2022, 11(3), 532; https://doi.org/10.3390/cells11030532 - 03 Feb 2022
Cited by 4 | Viewed by 2556
Abstract
Pneumonia is a leading cause of morbidity and mortality. While inflammation is a host protective response that ensures bacterial clearance, a finely regulated response is necessary to prevent bystander tissue damage. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a GC-induced protein with anti-inflammatory and [...] Read more.
Pneumonia is a leading cause of morbidity and mortality. While inflammation is a host protective response that ensures bacterial clearance, a finely regulated response is necessary to prevent bystander tissue damage. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a GC-induced protein with anti-inflammatory and proresolving bioactions, yet the therapeutical role of GILZ in infectious diseases remains unexplored. Herein, we investigate the role and effects of GILZ during acute lung injury (ALI) induced by LPS and Streptococcus pneumoniae infection. GILZ deficient mice (GILZ−/−) presented more severe ALI, characterized by increased inflammation, decreased macrophage efferocytosis and pronounced lung damage. In contrast, pulmonary inflammation, and damage were attenuated in WT mice treated with TAT-GILZ fusion protein. During pneumococcal pneumonia, TAT-GILZ reduced neutrophilic inflammation and prevented the associated lung damage. There was also enhanced macrophage efferocytosis and bacterial clearance in TAT-GILZ-treated mice. Mechanistically, TAT-GILZ enhanced macrophage phagocytosis of pneumococcus, which was lower in GILZ−/− macrophages. Noteworthy, early treatment with TAT-GILZ rescued 30% of S. pneumoniae-infected mice from lethal pneumonia. Altogether, we present evidence that TAT-GILZ enhances host resilience and resistance to pneumococcal pneumonia by controlling pulmonary inflammation and bacterial loads leading to decreased lethality. Exploiting GILZ pathways holds promise for the treatment of severe respiratory infections. Full article
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2021

Jump to: 2023, 2022

20 pages, 4515 KiB  
Review
GILZ as a Regulator of Cell Fate and Inflammation
by Stefano Bruscoli, Carlo Riccardi and Simona Ronchetti
Cells 2022, 11(1), 122; https://doi.org/10.3390/cells11010122 - 30 Dec 2021
Cited by 18 | Viewed by 3473
Abstract
One of the human body’s initial responses to stress is the adrenal response, involving the release of mediators that include adrenaline and glucocorticoids (GC). GC are involved in controlling the inflammatory and immune response mechanisms. Of these, the molecular mechanisms that contribute to [...] Read more.
One of the human body’s initial responses to stress is the adrenal response, involving the release of mediators that include adrenaline and glucocorticoids (GC). GC are involved in controlling the inflammatory and immune response mechanisms. Of these, the molecular mechanisms that contribute to anti-inflammatory effects warrant more investigation. Previously, we found that GC induced GILZ (glucocorticoid-induced leucine zipper) quickly and widely in thymocytes, T lymphocytes, and other leukocytes. GILZ regulates the activation of cells and is an essential mediator of endogenous GC and the majority of GC anti-inflammatory effects. Further research in this regard could lead to the development of an anti-inflammatory treatment that yields the therapeutic outcomes of GC but without their characteristic adverse effects. Here, we examine the mechanisms of GILZ in the context of GC. Specifically, we review its role in the proliferation and differentiation of cells and in apoptosis. We also examine its involvement in immune cells (macrophages, neutrophils, dendritic cells, T and B lymphocytes), and in non-immune cells, including cancer cells. In conclusion, GILZ is an anti-inflammatory molecule that could mediate the immunomodulatory activities of GC, with less adverse effects, and could be a target molecule for designing new therapies to treat inflammatory diseases. Full article
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14 pages, 2543 KiB  
Article
Impaired Glucocorticoid Receptor Signaling Aggravates Lung Injury after Hemorrhagic Shock
by Jonathan M. Preuss, Ute Burret, Michael Gröger, Sandra Kress, Angelika Scheuerle, Peter Möller, Jan P. Tuckermann, Martin Wepler and Sabine Vettorazzi
Cells 2022, 11(1), 112; https://doi.org/10.3390/cells11010112 - 30 Dec 2021
Cited by 2 | Viewed by 1797
Abstract
We previously showed that attenuated lung injury after hemorrhagic shock (HS) coincided with enhanced levels of the glucocorticoid (GC) receptor (GR) in lung tissue of swine. Here, we investigated the effects of impaired GR signaling on the lung during resuscitated HS using a [...] Read more.
We previously showed that attenuated lung injury after hemorrhagic shock (HS) coincided with enhanced levels of the glucocorticoid (GC) receptor (GR) in lung tissue of swine. Here, we investigated the effects of impaired GR signaling on the lung during resuscitated HS using a dysfunctional GR mouse model (GRdim/dim). In a mouse intensive care unit, HS led to impaired lung mechanics and aggravated lung inflammation in GRdim/dim mice compared to wildtype mice (GR+/+). After HS, high levels of the pro-inflammatory and pro-apoptotic transcription factor STAT1/pSTAT1 were found in lung samples from GRdim/dim mice. Lungs of GRdim/dim mice revealed apoptosis, most likely as consequence of reduced expression of the lung-protective Angpt1 compared to GR+/+ after HS. RNA-sequencing revealed increased expression of pro-apoptotic and cytokine-signaling associated genes in lung tissue of GRdim/dim mice. Furthermore, high levels of pro-inflammatory cytokines and iNOS were found in lungs of GRdim/dim mice. Our results indicate impaired repression of STAT1/pSTAT1 due to dysfunctional GR signaling in GRdim/dim mice, which leads to increased inflammation and apoptosis in the lungs. These data highlight the crucial role of functional GR signaling to attenuate HS-induced lung damage. Full article
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14 pages, 829 KiB  
Review
From NSAIDs to Glucocorticoids and Beyond
by Ajantha Sinniah, Samia Yazid and Rod J. Flower
Cells 2021, 10(12), 3524; https://doi.org/10.3390/cells10123524 - 14 Dec 2021
Cited by 28 | Viewed by 5375
Abstract
Our interest in inflammation and its treatment stems from ancient times. Hippocrates used willow bark to treat inflammation, and many centuries later, salicylic acid and its derivative aspirin’s ability to inhibit cyclooxygenase enzymes was discovered. Glucocorticoids (GC) ushered in a new era of [...] Read more.
Our interest in inflammation and its treatment stems from ancient times. Hippocrates used willow bark to treat inflammation, and many centuries later, salicylic acid and its derivative aspirin’s ability to inhibit cyclooxygenase enzymes was discovered. Glucocorticoids (GC) ushered in a new era of treatment for both chronic and acute inflammatory disease, but their potentially dangerous side effects led the pharmaceutical industry to seek other, safer, synthetic GC drugs. The discovery of the GC-inducible endogenous anti-inflammatory protein annexin A1 (AnxA1) and other endogenous proresolving mediators has opened a new era of anti-inflammatory therapy. This review aims to recapitulate the last four decades of research on NSAIDs, GCs, and AnxA1 and their anti-inflammatory effects. Full article
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19 pages, 1438 KiB  
Review
Therapeutic Potential of Annexin A1 Modulation in Kidney and Cardiovascular Disorders
by Mahmood S. Mozaffari
Cells 2021, 10(12), 3420; https://doi.org/10.3390/cells10123420 - 05 Dec 2021
Cited by 8 | Viewed by 2920
Abstract
Renal and cardiovascular disorders are very prevalent and associated with significant morbidity and mortality. Among diverse pathogenic mechanisms, the dysregulation of immune and inflammatory responses plays an essential role in such disorders. Consequently, the discovery of Annexin A1, as a glucocorticoid-inducible anti-inflammatory protein, [...] Read more.
Renal and cardiovascular disorders are very prevalent and associated with significant morbidity and mortality. Among diverse pathogenic mechanisms, the dysregulation of immune and inflammatory responses plays an essential role in such disorders. Consequently, the discovery of Annexin A1, as a glucocorticoid-inducible anti-inflammatory protein, has fueled investigation of its role in renal and cardiovascular pathologies. Indeed, with respect to the kidney, its role has been examined in diverse renal pathologies, including acute kidney injury, diabetic nephropathy, immune-mediated nephropathy, drug-induced kidney injury, kidney stone formation, and renal cancer. Regarding the cardiovascular system, major areas of investigation include the role of Annexin A1 in vascular abnormalities, atherosclerosis, and myocardial infarction. Thus, this review briefly describes major structural and functional features of Annexin A1 followed by a review of its role in pathologies of the kidney and the cardiovascular system, as well as the therapeutic potential of its modulation for such disorders. Full article
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20 pages, 3499 KiB  
Article
Multi-Tissue Characterization of GILZ Expression in Dendritic Cell Subsets at Steady State and in Inflammatory Contexts
by Molène Docq, Mathias Vétillard, Carmen Gallego, Agnieszka Jaracz-Ros, Françoise Mercier-Nomé, Françoise Bachelerie and Géraldine Schlecht-Louf
Cells 2021, 10(11), 3153; https://doi.org/10.3390/cells10113153 - 13 Nov 2021
Viewed by 2436
Abstract
Dendritic cells (DCs) are key players in the control of tolerance and immunity. Glucocorticoids (GCs) are known to regulate DC function by promoting their tolerogenic differentiation through the induction of inhibitory ligands, cytokines, and enzymes. The GC-induced effects in DCs were shown to [...] Read more.
Dendritic cells (DCs) are key players in the control of tolerance and immunity. Glucocorticoids (GCs) are known to regulate DC function by promoting their tolerogenic differentiation through the induction of inhibitory ligands, cytokines, and enzymes. The GC-induced effects in DCs were shown to critically depend on increased expression of the Glucocorticoid-Induced Leucine Zipper protein (GILZ). GILZ expression levels were further shown to control antigen-presenting cell function, as well as T-cell priming capacity of DCs. However, the pattern of GILZ expression in DC subsets across tissues remains poorly described, as well as the modulation of its expression levels in different pathological settings. To fill in this knowledge gap, we conducted an exhaustive analysis of GILZ relative expression levels in DC subsets from various tissues using multiparametric flow cytometry. This study was performed at steady state, in the context of acute as well as chronic skin inflammation, and in a model of cancer. Our results show the heterogeneity of GILZ expression among DC subsets as well as the complexity of its modulation, that varies in a cell subset- and context-specific manner. Considering the contribution of GILZ in the control of DC functions and its potential as an immune checkpoint in cancer settings, these results are of high relevance for optimal GILZ targeting in therapeutic strategies. Full article
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14 pages, 1595 KiB  
Article
Glucocorticoid-Induced Leucine Zipper-Mediated TLR2 Downregulation Accounts for Reduced Neutrophil Activity Following Acute DEX Treatment
by Erika Ricci, Elena Roselletti, Marco Gentili, Samuele Sabbatini, Stefano Perito, Carlo Riccardi, Graziella Migliorati, Claudia Monari and Simona Ronchetti
Cells 2021, 10(9), 2228; https://doi.org/10.3390/cells10092228 - 28 Aug 2021
Cited by 5 | Viewed by 1891
Abstract
Glucocorticoids are the most powerful anti-inflammatory and immunosuppressive pharmacological drugs available, despite their adverse effects. Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced gene that shares several anti-inflammatory properties with glucocorticoids. Although immunosuppressive effects of glucocorticoids on neutrophils remain poorly understood, we previously demonstrated [...] Read more.
Glucocorticoids are the most powerful anti-inflammatory and immunosuppressive pharmacological drugs available, despite their adverse effects. Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced gene that shares several anti-inflammatory properties with glucocorticoids. Although immunosuppressive effects of glucocorticoids on neutrophils remain poorly understood, we previously demonstrated that GILZ suppresses neutrophil activation under glucocorticoid treatment. Here, we sought to explore the regulation of Toll-like receptor 2 (TLR2) by the synthetic glucocorticoid dexamethasone (DEX) on neutrophils and the associated GILZ involvement. Peripheral blood neutrophils were isolated from wild type and GILZ-knock-out (KO) mice. TLR2 was found to be downregulated by the in vivo administration of glucocorticoids in wild type but not in GILZ-KO neutrophils, suggesting the involvement of GILZ in TLR2 downregulation. Accordingly, the TLR2-associated anti-fungal activity of neutrophils was reduced by DEX treatment in wild type but not GILZ-KO neutrophils. Furthermore, GILZ did not interact with NF-κB but was found to bind with STAT5, a pivotal factor in the regulation of TLR2 expression. A similar modulation of TLR2 expression, impaired phagocytosis, and killing activity was observed in circulating human neutrophils treated in vitro with DEX. These results demonstrate that glucocorticoids reduce the ability of neutrophils to respond to infections by downregulating TLR2 via GILZ, thereby reducing critical functions. Full article
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13 pages, 684 KiB  
Review
Glucocorticoid-Induced Leucine Zipper (GILZ) in Cardiovascular Health and Disease
by Donato Cappetta, Oxana Bereshchenko, Eleonora Cianflone, Francesco Rossi, Carlo Riccardi, Daniele Torella, Liberato Berrino, Konrad Urbanek, Antonella De Angelis and Stefano Bruscoli
Cells 2021, 10(8), 2155; https://doi.org/10.3390/cells10082155 - 21 Aug 2021
Cited by 3 | Viewed by 2715
Abstract
Glucocorticoids (GCs) are essential in regulating functions and homeostasis in many biological systems and are extensively used to treat a variety of conditions associated with immune/inflammatory processes. GCs are among the most powerful drugs for the treatment of autoimmune and inflammatory diseases, but [...] Read more.
Glucocorticoids (GCs) are essential in regulating functions and homeostasis in many biological systems and are extensively used to treat a variety of conditions associated with immune/inflammatory processes. GCs are among the most powerful drugs for the treatment of autoimmune and inflammatory diseases, but their long-term usage is limited by severe adverse effects. For this reason, to envision new therapies devoid of typical GC side effects, research has focused on expanding the knowledge of cellular and molecular effects of GCs. GC-induced leucine zipper (GILZ) is a GC-target protein shown to mediate several actions of GCs, including inhibition of the NF-κB and MAPK pathways. GILZ expression is not restricted to immune cells, and it has been shown to play a regulatory role in many organs and tissues, including the cardiovascular system. Research on the role of GILZ on endothelial cells has demonstrated its ability to modulate the inflammatory cascade, resulting in a downregulation of cytokines, chemokines, and cellular adhesion molecules. GILZ also has the capacity to protect myocardial cells, as its deletion makes the heart, after a deleterious stimulus, more susceptible to apoptosis, immune cell infiltration, hypertrophy, and impaired function. Despite these advances, we have only just begun to appreciate the relevance of GILZ in cardiovascular homeostasis and dysfunction. This review summarizes the current understanding of the role of GILZ in modulating biological processes relevant to cardiovascular biology. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.





 

 

 

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