Biomolecules

Research

20 pages, 2528 KB

Open AccessArticle

Akkermansia muciniphila- and Pathogenic Bacteria-Derived Endotoxins Differently Regulate Human Dendritic Cell Generation and γδ T Lymphocyte Activation

by Veronica Fertitta, Barbara Varano, Manuela Del Cornò, Paola Fortini, Anna Aureli and Lucia Conti

Biomolecules 2024, 14(12), 1571; https://doi.org/10.3390/biom14121571 - 9 Dec 2024

Cited by 1 | Viewed by 1888

Abstract

Lipopolysaccharide (LPS) is a potent endotoxin released at high concentrations in acute infections, causing massive host inflammatory response. Accumulating evidence indicates that dysbiosis-associated chronic low levels of circulating LPS can sustain a prolonged sterile low-grade inflammation that increases the risk of several non-communicable [...] Read more.

Lipopolysaccharide (LPS) is a potent endotoxin released at high concentrations in acute infections, causing massive host inflammatory response. Accumulating evidence indicates that dysbiosis-associated chronic low levels of circulating LPS can sustain a prolonged sterile low-grade inflammation that increases the risk of several non-communicable diseases. Interventions aimed at increasing the abundance of beneficial/probiotic bacteria, including Akkermansia muciniphila, result in reduced inflammation, favoring metabolic and immune health. Immunosuppression is a common feature in conditions of chronic inflammation, and dendritic cells (DCs) represent key targets given their ability to shift the balance toward immunity or tolerance. In this study, the effects of low concentrations of LPS from pathogenic (Escherichia coli and Salmonella enterica) and probiotic (Akkermansia muciniphila) bacterial species on human DC generation and functions were compared. We report that monocyte precursor priming with Escherichia coli and Salmonella enterica LPS forces the differentiation of PD-L1-expressing DCs, releasing high levels of IL-6 and IL-10, and impairs their capacity to drive full TCR-Vδ2 T cell activation. Conversely, comparable concentrations of Akkermansia muciniphila promoted the generation of DCs with preserved activating potential and immunostimulatory properties. These results shed light on potential mechanisms underlying the impact of low endotoxemia on disease risk and pathogenesis, and increase our understanding of the immunomodulatory effects of Akkermansia muciniphila. Full article

(This article belongs to the Special Issue Insights of Innate Immunology into Inflammation and Infections)

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21 pages, 3434 KB

Open AccessArticle

Design of a Robust Flow Cytometric Approach for Phenotypical and Functional Analysis of Human Monocyte Subsets in Health and Disease

by Talia Ahrazoglu, Jennifer Isabel Kluczny, Patricia Kleimann, Lisa-Marie Irschfeld, Fabian Theodor Nienhaus, Florian Bönner, Norbert Gerdes and Sebastian Temme

Biomolecules 2024, 14(10), 1251; https://doi.org/10.3390/biom14101251 - 3 Oct 2024

Cited by 1 | Viewed by 3953

Abstract

Human monocytes can be subdivided into phenotypically and functionally different classical, intermediate and non-classical monocytes according to the cell surface expression of CD14 and CD16. A precise identification and characterisation of monocyte subsets is necessary to unravel their role in inflammatory diseases. Here, [...] Read more.

Human monocytes can be subdivided into phenotypically and functionally different classical, intermediate and non-classical monocytes according to the cell surface expression of CD14 and CD16. A precise identification and characterisation of monocyte subsets is necessary to unravel their role in inflammatory diseases. Here, we compared three different flow cytometric strategies (A–C) and found that strategy C, which included staining against CD11b, HLA-DR, CD14 and CD16, followed by several gating steps, most reliably identified monocyte subtypes in blood samples from healthy volunteers and from patients with stable coronary heart disease (CHD) or ST-elevation myocardial infarction (STEMI). Additionally, we established a fixation and permeabilisation protocol to enable the analysis of intracellular markers. We investigated the phagocytosis of lipid nanoparticles, the uptake of 2-NBD-glucose and the intracellular levels of CD74 and HLA-DM. This revealed that classical and intermediate monocytes from patients with STEMI showed the highest uptake of 2-NBD-glucose, whereas classical and intermediate monocytes from patients with CHD took up the largest amounts of lipid nanoparticles. Interestingly, intermediate monocytes had the highest expression level of HLA-DM. Taken together, we present a robust flow cytometric approach for the identification and functional characterisation of monocyte subtypes in healthy humans and patients with diseases. Full article

(This article belongs to the Special Issue Insights of Innate Immunology into Inflammation and Infections)

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23 pages, 12352 KB

Open AccessArticle

Predicting Regression of Barrett’s Esophagus—Can All the King’s Men Put It Together Again?

by Martin Tobi, Nabiha Khoury, Omar Al-Subee, Seema Sethi, Harvinder Talwar, Michael Kam, James Hatfield, Edi Levi, Jason Hallman, Mary Pat Moyer, Laura Kresty, Michael J. Lawson and Benita McVicker

Biomolecules 2024, 14(9), 1182; https://doi.org/10.3390/biom14091182 - 20 Sep 2024

Cited by 3 | Viewed by 1822

Abstract

The primary pre-neoplastic lesion of the lower esophagus in the vicinity of the gastroesophageal junction (GEJ) is any Barrett’s esophageal lesions (BE), and esophageal neoplasia has increased in the US population with predispositions (Caucasian males, truncal obesity, age, and GERD). The responses to [...] Read more.

The primary pre-neoplastic lesion of the lower esophagus in the vicinity of the gastroesophageal junction (GEJ) is any Barrett’s esophageal lesions (BE), and esophageal neoplasia has increased in the US population with predispositions (Caucasian males, truncal obesity, age, and GERD). The responses to BE are endoscopic and screening cytologic programs with endoscopic ablation of various forms. The former have not been proven to be cost-effective and there are mixed results for eradication. A fresh approach is sorely needed. We prospectively followed 2229 mostly male veterans at high risk for colorectal cancer in a 27-year longitudinal long-term study, collecting data on colorectal neoplasia development and other preneoplastic lesions, including BE and spontaneous regression (SR). Another cross-sectional BE study at a similar time period investigated antigenic changes at the GEJ in both BE glandular and squamous mucosa immunohistochemistry and the role of inflammation. Ten of the prospective cohort (21.7%) experienced SR out of a total of forty-six BE patients. Significant differences between SR and stable BE were younger age (p < 0.007); lower platelet levels (p < 0.02); rectal p87 elevation in SR (p < 0.049); a reduced innate immune system (InImS) FEREFF ratio (ferritin: p87 colonic washings) (p < 0.04). Ancillary testing showed a broad range of neoplasia biomarkers. InImS markers may be susceptible to intervention using commonplace and safe medical interventions and encourage SR. Full article

(This article belongs to the Special Issue Insights of Innate Immunology into Inflammation and Infections)

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12 pages, 2154 KB

Open AccessArticle

Cytokines from SARS-CoV-2 Spike-Activated Macrophages Hinder Proliferation and Cause Cell Dysfunction in Endothelial Cells

by Giulia Recchia Luciani, Amelia Barilli, Rossana Visigalli, Valeria Dall’Asta and Bianca Maria Rotoli

Biomolecules 2024, 14(8), 927; https://doi.org/10.3390/biom14080927 - 30 Jul 2024

Cited by 4 | Viewed by 1643

Abstract

Endothelial dysfunction plays a central role in the severity of COVID-19, since the respiratory, thrombotic and myocardial complications of the disease are closely linked to vascular endothelial damage. To address this issue, we evaluate here the effect of conditioned media from spike S1-activated [...] Read more.

Endothelial dysfunction plays a central role in the severity of COVID-19, since the respiratory, thrombotic and myocardial complications of the disease are closely linked to vascular endothelial damage. To address this issue, we evaluate here the effect of conditioned media from spike S1-activated macrophages (CM_S1) on the proliferation of human umbilical endothelial cells (HUVECs), focusing on the specific role of interleukin-1-beta (IL-1β), interleukin-6 (IL-6), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Results obtained demonstrate that the incubation with CM_S1 for 72 h hinders endothelial cell proliferation and induces signs of cytotoxicity. Comparable results are obtained upon exposure to IFN-γ + TNF-α, which are thus postulated to play a pivotal role in the effects observed. These events are associated with an increase in p21 protein and a decrease in Rb phosphorylation, as well as with the activation of IRF-1 and NF-kB transcription factors. Overall, these findings further sustain the pivotal role of a hypersecretion of inflammatory cytokines as a trigger for endothelial activation and injury in the immune-mediated effects of COVID-19. Full article

(This article belongs to the Special Issue Insights of Innate Immunology into Inflammation and Infections)

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12 pages, 2054 KB

Open AccessArticle

Monitoring Circulating Myeloid Cells in Peritonitis with an In Vivo Imaging Flow Cytometer

by Sunitha Pulikkot, Souvik Paul, Alexxus Hall, Brianna Gardner, Wei Liu, Liang Hu, Anthony T. Vella, Yunfeng Chen and Zhichao Fan

Biomolecules 2024, 14(8), 886; https://doi.org/10.3390/biom14080886 - 23 Jul 2024

Cited by 2 | Viewed by 1992

Abstract

Peritonitis is a common and life-threatening inflammatory disease. Myeloid cells are elevated in the peripheral blood and contribute to peritonitis, but their circulating dynamics are not clear. In vivo flow cytometry (IVFC) is a noninvasive technique for monitoring the dynamics of circulating cells [...] Read more.

Peritonitis is a common and life-threatening inflammatory disease. Myeloid cells are elevated in the peripheral blood and contribute to peritonitis, but their circulating dynamics are not clear. In vivo flow cytometry (IVFC) is a noninvasive technique for monitoring the dynamics of circulating cells in live animals. It has been extensively used to detect circulating tumor cells, but rarely for monitoring immune cells. Here, we describe a method adapting an intravital microscope for IVFC so that we can monitor LysM-EGFP-labeled circulating myeloid cells in a tumor necrosis factor (TNF) α-induced peritonitis mouse model. Using this IVFC method, we quantified the blood flow velocity and cell concentration in circulation. We observed a significant increase in LysM-EGFP+ cells in circulation after TNFα intraperitoneal (i.p.) injection, which reached a plateau in ~20 min. Conventional cytometry analysis showed that most LysM-EGFP+ cells were neutrophils. Increasing blood neutrophils were accompanied by neutrophil recruitment to the peritoneal cavity and neutrophil emigration from the bone marrow. We then monitored neutrophil CD64 expression in vivo and found a significant increase in TNFα-induced peritonitis. We also found that CD18 blockade doubled the circulating neutrophil number in TNFα-induced peritonitis, suggesting that CD18 is critical for neutrophil recruitment in peritonitis. Overall, we demonstrate that IVFC techniques are useful for studying the circulating dynamics of immune cells during inflammatory diseases. Full article

(This article belongs to the Special Issue Insights of Innate Immunology into Inflammation and Infections)

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Review

Jump to: Research, Other

13 pages, 1179 KB

Open AccessReview

Biomarkers for Serious Bacterial Infections in Febrile Children

by Luca Bernardi, Gianluca Bossù, Giulia Dal Canto, Giuliana Giannì and Susanna Esposito

Biomolecules 2024, 14(1), 97; https://doi.org/10.3390/biom14010097 - 12 Jan 2024

Cited by 5 | Viewed by 6541

Abstract

Febrile infections in children are a common cause of presentation to the emergency department (ED). While viral infections are usually self-limiting, sometimes bacterial illnesses may lead to sepsis and severe complications. Inflammatory biomarkers such as C reactive protein (CRP) and procalcitonin are usually [...] Read more.

Febrile infections in children are a common cause of presentation to the emergency department (ED). While viral infections are usually self-limiting, sometimes bacterial illnesses may lead to sepsis and severe complications. Inflammatory biomarkers such as C reactive protein (CRP) and procalcitonin are usually the first blood exams performed in the ED to differentiate bacterial and viral infections; nowadays, a better understanding of immunochemical pathways has led to the discovery of new and more specific biomarkers that could play a role in the emergency setting. The aim of this narrative review is to provide the most recent evidence on biomarkers and predictor models, combining them for serious bacterial infection (SBI) diagnosis in febrile children. Literature analysis shows that inflammatory response is a complex mechanism in which many biochemical and immunological factors contribute to the host response in SBI. CRP and procalcitonin still represent the most used biomarkers in the pediatric ED for the diagnosis of SBI. Their sensibility and sensitivity increase when combined, and for this reason, it is reasonable to take them both into consideration in the evaluation of febrile children. The potential of machine learning tools, which represent a real novelty in medical practice, in conjunction with routine clinical and biological information, may improve the accuracy of diagnosis and target therapeutic options in SBI. However, studies on this matter are not yet validated in younger populations, making their relevance in pediatric precision medicine still uncertain. More data from further research are needed to improve clinical practice and decision making using these new technologies. Full article

(This article belongs to the Special Issue Insights of Innate Immunology into Inflammation and Infections)

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23 pages, 445 KB

Open AccessReview

Targeting Neutrophil β₂-Integrins: A Review of Relevant Resources, Tools, and Methods

by Haleigh E. Conley and M. Katie Sheats

Biomolecules 2023, 13(6), 892; https://doi.org/10.3390/biom13060892 - 26 May 2023

Cited by 14 | Viewed by 3393

Abstract

Neutrophils are important innate immune cells that respond during inflammation and infection. These migratory cells utilize β₂-integrin cell surface receptors to move out of the vasculature into inflamed tissues and to perform various anti-inflammatory responses. Although critical for fighting off infection, [...] Read more.

Neutrophils are important innate immune cells that respond during inflammation and infection. These migratory cells utilize β₂-integrin cell surface receptors to move out of the vasculature into inflamed tissues and to perform various anti-inflammatory responses. Although critical for fighting off infection, neutrophil responses can also become dysregulated and contribute to disease pathophysiology. In order to limit neutrophil-mediated damage, investigators have focused on β₂-integrins as potential therapeutic targets, but so far these strategies have failed in clinical trials. As the field continues to move forward, a better understanding of β₂-integrin function and signaling will aid the design of future therapeutics. Here, we provide a detailed review of resources, tools, experimental methods, and in vivo models that have been and will continue to be utilized to investigate the vitally important cell surface receptors, neutrophil β₂-integrins. Full article

(This article belongs to the Special Issue Insights of Innate Immunology into Inflammation and Infections)

Other

Jump to: Research, Review

11 pages, 1065 KB

Open AccessHypothesis

Does SARS-CoV-2 Induce IgG4 Synthesis to Evade the Immune System?

by Alberto Rubio-Casillas, Elrashdy M. Redwan and Vladimir N. Uversky

Biomolecules 2023, 13(9), 1338; https://doi.org/10.3390/biom13091338 - 1 Sep 2023

Cited by 9 | Viewed by 6880

Abstract

SARS-CoV-2, the virus that causes the COVID-19 disease, has been shown to cause immune suppression in certain individuals. This can manifest as a reduced ability of the host’s immune system to effectively control the infection. Studies have reported that patients with COVID-19 can [...] Read more.

SARS-CoV-2, the virus that causes the COVID-19 disease, has been shown to cause immune suppression in certain individuals. This can manifest as a reduced ability of the host’s immune system to effectively control the infection. Studies have reported that patients with COVID-19 can exhibit a decline in white blood cell counts, including natural killer cells and T cells, which are integral components of the immune system’s response to viral pathogens. These cells play critical roles in the immune response to viral infections, and their depletion can make it harder for the body to mount an effective defense against the virus. Additionally, the virus can also directly infect immune cells, further compromising their ability to function. Some individuals with severe COVID-19 pneumonia may develop a “cytokine storm”, an overactive immune response that may result in tissue damage and organ malfunction. The underlying mechanisms of immune suppression in SARS-CoV-2 are not entirely understood at this time, and research is being conducted to gain a more comprehensive understanding. Research has shown that severe SARS-CoV-2 infection promotes the synthesis of IgG4 antibodies. In this study, we propose the hypothesis that IgG4 antibodies produced by B cells in response to infection by SARS-CoV-2 generate immunological tolerance, which prevents its elimination and leads to persistent and chronic infection. In summary, we believe that this constitutes another immune evasion mechanism that bears striking similarities to that developed by cancer cells to evade immune surveillance. Full article

(This article belongs to the Special Issue Insights of Innate Immunology into Inflammation and Infections)

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