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Viruses May 2024Interferons (IFNs) are antiviral cytokines that defend against viral infections by inducing the expression of interferon-stimulated genes (ISGs). Interferon-inducible... (Review)
Review
Interferons (IFNs) are antiviral cytokines that defend against viral infections by inducing the expression of interferon-stimulated genes (ISGs). Interferon-inducible transmembrane proteins (IFITMs) 1, 2, and 3 are crucial ISG products and members of the CD225 protein family. Compelling evidence shows that IFITMs restrict the infection of many unrelated viruses by inhibiting the virus-cell membrane fusion at the virus entry step via the modulation of lipid composition and membrane properties. Meanwhile, viruses can evade IFITMs' restrictions by either directly interacting with IFITMs via viral glycoproteins or by altering the native entry pathway. At the same time, cumulative evidence suggests context-dependent and multifaceted roles of IFITMs in modulating virus infections and cell signaling. Here, we review the diverse antiviral mechanisms of IFITMs, the viral antagonizing strategies, and the regulation of IFITM activity in host cells. The mechanisms behind the antiviral activity of IFITMs could aid the development of broad-spectrum antivirals and enhance preparedness for future pandemics.
Topics: Humans; Membrane Proteins; Interferons; Virus Internalization; Antiviral Agents; Immune Evasion; Animals; Virus Diseases; Viruses; Host-Pathogen Interactions; Signal Transduction; Antigens, Differentiation
PubMed: 38793616
DOI: 10.3390/v16050734 -
Transplantation Feb 2017We have previously reported on a novel organ-specific immunomodifying therapy that provides protection from early allograft rejection in the absence of systemic...
BACKGROUND
We have previously reported on a novel organ-specific immunomodifying therapy that provides protection from early allograft rejection in the absence of systemic immunosuppressive drugs. This novel therapy is a nanobarrier membrane called ImmunoCloak, consisting of a matrix of laminin, proteoglycans, fibronectin, and collagens. The membrane "immunocloaks" the luminal surfaces within the renal vasculature by covering the point of contact between donor vascular endothelial cells and the recipient's immune cells, without adversely affecting renal function. The resulting nonthrombogenic and nonimmunogenic apical surface significantly delays the onset of rejection fivefold over untreated controls. Currently, our focus is to elucidate the mechanisms of protection provided by placement of the membrane.
METHODS
The mechanisms underlying the protective effect of the ImmunoCloak treatment was evaluated using human peripheral blood mononuclear cells and by testing for antigen presentation by cytokine/chemokine analysis using the Luminex platform, T cell allogeneic responses were measured by flow cytometry, and diapedesis was assessed using transwell plates.
RESULTS
We now report that ImmunoCloak interrupts antigen presentation thereby preventing early T cell activation and interferes with diapedesis. There was significant inhibition in the synthesis of proinflammatory cytokines with a concordant blockade of T cell-mediated responses. The placement of the ImmunoCloak also significantly reduced leukocyte migration through the endothelial cell layer by 93%.
CONCLUSIONS
Eliminating the need for nephrotoxic immunosuppressive drugs during the early posttransplant period could help to ameliorate the severity of delayed graft function and could provide a path to using more ischemically damaged renal allografts.
Topics: Allografts; Antigen Presentation; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Cell Proliferation; Cells, Cultured; Coculture Techniques; Collagen; Extracellular Matrix Proteins; Fibronectins; Graft Rejection; Human Umbilical Vein Endothelial Cells; Humans; Immunotherapy; Laminin; Lectins, C-Type; Lymphocyte Activation; Membranes, Artificial; Nanoparticles; Proteoglycans; T-Lymphocytes; Time Factors; Transendothelial and Transepithelial Migration
PubMed: 27764033
DOI: 10.1097/TP.0000000000001537 -
Journal of Tissue Engineering and... Jul 2019Shipping time and shipping delays might affect the quality of the stem cells based engineered "organs." In our laboratory, we have developed a limbal stem cell deficient...
Shipping time and shipping delays might affect the quality of the stem cells based engineered "organs." In our laboratory, we have developed a limbal stem cell deficient (LSCD) rabbit model. To reverse the LSCD, we cultured oral mucosal epithelial cells for 2-3 weeks and engineered cultured autologous oral mucosa epithelial cell sheets (CAOMECS), which were grafted on the LSCD cornea. The purpose of this study was to vitrify CAOMECS and to store it until the CAOMECS can be grafted onto patients. CAOMECS were vitrified in LN for up to 204 days. We tested two different methods of vitrification with different solutions; however, CAOMECS were only viable when they were not stored in a vitrification solution; results were only reported from this CAOMECS. On the basis of hematoxylin and eosin staining, we showed that the CAOMECS morphology was well preserved after long-term storage in LN . Most of the preservation solutions maintained the CAOMECS phenotype (Ki67, proliferating cell nuclear antigen (PCNA), Beta-Catenin, ZO-1, E-Cadherin, CK3, CK4, CK13). The exception was the solution composed with ethylene glycol and Dimethyl sulfoxide (DMSO): this resulted in loss of DeltaN-p63 expression. DeltaN-p63 is an important marker for cell proliferation. The expression of proteins involved in cell-cell connection and the differentiation markers were maintained. Apoptosis was not detected in the thawed CAOMECS. We demonstrated that CAOMECS can be stored long-term in LN without affecting their morphology and phenotype.
Topics: Animals; Antigens, Differentiation; Epithelial Cells; Gene Expression Regulation; Mouth Mucosa; Preservation, Biological; Rabbits
PubMed: 30964962
DOI: 10.1002/term.2864 -
Movement Disorders : Official Journal... Apr 2021Parkinson's disease (PD) is a neurodegenerative disorder with a significant immune component, as demonstrated by changes in immune biomarkers in patients' biofluids....
BACKGROUND
Parkinson's disease (PD) is a neurodegenerative disorder with a significant immune component, as demonstrated by changes in immune biomarkers in patients' biofluids. However, which specific cells are responsible for those changes is unclear because most immune biomarkers can be produced by various cell types.
OBJECTIVES
The aim of this study was to explore monocyte involvement in PD.
METHODS
We investigated the monocyte-specific biomarker sCD163, the soluble form of the receptor CD163, in cerebrospinal fluid (CSF) and serum in two experiments, and compared it with other biomarkers and clinical data. Potential connections between CD163 and alpha-synuclein were studied in vitro.
RESULTS
CSF-sCD163 increased in late-stage PD and correlated with the PD biomarkers alpha-synuclein, Tau, and phosphorylated Tau, whereas it inversely correlated with the patients' cognitive scores, supporting monocyte involvement in neurodegeneration and cognition in PD. Serum-sCD163 increased only in female patients, suggesting a sex-distinctive monocyte response. CSF-sCD163 also correlated with molecules associated with adaptive and innate immune system activation and with immune cell recruitment to the brain. Serum-sCD163 correlated with proinflammatory cytokines and acute-phase proteins, suggesting a relation to chronic systemic inflammation. Our in vitro study showed that alpha-synuclein activates macrophages and induces shedding of sCD163, which in turn enhances alpha-synuclein uptake by myeloid cells, potentially participating in its clearance.
CONCLUSIONS
Our data present sCD163 as a potential cognition-related biomarker in PD and suggest a role for monocytes in both peripheral and brain immune responses. This may be directly related to alpha-synuclein's proinflammatory capacity but could also have consequences for alpha-synuclein processing. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Amyloid beta-Peptides; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Cognition; Female; Humans; Monocytes; Parkinson Disease; Peptide Fragments; Receptors, Cell Surface; alpha-Synuclein
PubMed: 33332647
DOI: 10.1002/mds.28424 -
PloS One 2020The Rho GTPase RAC1 is an important regulator of cytoskeletal dynamics, but the role of macrophage-specific RAC1 has not been explored during atherogenesis. We analyzed...
The Rho GTPase RAC1 is an important regulator of cytoskeletal dynamics, but the role of macrophage-specific RAC1 has not been explored during atherogenesis. We analyzed RAC1 expression in human carotid atherosclerotic plaques using immunofluorescence and found higher macrophage RAC1 expression in advanced plaques compared with intermediate human atherosclerotic plaques. We then produced mice with Rac1-deficient macrophages by breeding conditional floxed Rac1 mice (Rac1fl/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis was studied in vivo by infecting Rac1fl/fl and Rac1fl/fl/LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Rac1fl/fl/LC macrophages secreted lower levels of IL-6 and TNF-α and exhibited reduced foam cell formation and lipid uptake. The deficiency of Rac1 in macrophages reduced the size of aortic atherosclerotic plaques in AdPCSK9-infected Rac1fl/fl/LC mice. Compare with controls, intima/media ratios, the size of necrotic cores, and numbers of CD68-positive macrophages in atherosclerotic plaques were reduced in Rac1-deficient mice. Moreover, we found that RAC1 interacts with actin-binding filamin A. Macrophages expressed increased RAC1 levels in advanced human atherosclerosis. Genetic inactivation of RAC1 impaired macrophage function and reduced atherosclerosis in mice, suggesting that drugs targeting RAC1 may be useful in the treatment of atherosclerosis.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Atherosclerosis; Cells, Cultured; Humans; Interleukin-6; Lipid Metabolism; Macrophages; Mice; Mice, Inbred C57BL; Neuropeptides; Tumor Necrosis Factor-alpha; rac1 GTP-Binding Protein
PubMed: 32941503
DOI: 10.1371/journal.pone.0239284 -
PLoS Neglected Tropical Diseases Nov 2018Scavenger Receptors (SRs) from the host's innate immune system are known to bind multiple ligands to promote the removal of non-self or altered-self targets. CD5 and CD6...
The ectodomains of the lymphocyte scavenger receptors CD5 and CD6 interact with tegumental antigens from Echinococcus granulosus sensu lato and protect mice against secondary cystic echinococcosis.
BACKGROUND
Scavenger Receptors (SRs) from the host's innate immune system are known to bind multiple ligands to promote the removal of non-self or altered-self targets. CD5 and CD6 are two highly homologous class I SRs mainly expressed on all T cells and the B1a cell subset, and involved in the fine tuning of activation and differentiation signals delivered by the antigen-specific receptors (TCR and BCR, respectively), to which they physically associate. Additionally, CD5 and CD6 have been shown to interact with and sense the presence of conserved pathogen-associated structures from bacteria, fungi and/or viruses.
METHODOLOGY/PRINCIPAL FINDINGS
We report herein the interaction of CD5 and CD6 lymphocyte surface receptors with Echinococcus granulosus sensu lato (s.l.). Binding studies show that both soluble and membrane-bound forms of CD5 and CD6 bind to intact viable protoscoleces from E. granulosus s.l. through recognition of metaperiodate-resistant tegumental components. Proteomic analyses allowed identification of thioredoxin peroxidase for CD5, and peptidyl-prolyl cis-trans isomerase (cyclophilin) and endophilin B1 (antigen P-29) for CD6, as their potential interactors. Further in vitro assays demonstrate that membrane-bound or soluble CD5 and CD6 forms differentially modulate the pro- and anti-inflammatory cytokine release induced following peritoneal cells exposure to E. granulosus s.l. tegumental components. Importantly, prophylactic infusion of soluble CD5 or CD6 significantly ameliorated the infection outcome in the mouse model of secondary cystic echinococcosis.
CONCLUSIONS/SIGNIFICANCE
Taken together, the results expand the pathogen binding properties of CD5 and CD6 and provide novel evidence for their therapeutic potential in human cystic echinococcosis.
Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; CD5 Antigens; Echinococcosis; Echinococcus granulosus; Female; Helminth Proteins; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protein Binding; Proteomics; Receptors, Scavenger; T-Lymphocytes
PubMed: 30500820
DOI: 10.1371/journal.pntd.0006891 -
Scientific Reports Jul 2018Severe alcoholic hepatitis (SAH) is associated with iron accumulation in hepatocytes/macrophages. This possibly correlates with inflammation and stress but the exact...
Severe alcoholic hepatitis (SAH) is associated with iron accumulation in hepatocytes/macrophages. This possibly correlates with inflammation and stress but the exact mechanism still remains obscure. To understand the role of iron and the mechanisms of systemic iron-overload, a transcriptomic study of liver and Peripheral Blood -Mononuclear-Cells (PBMCs) was undertaken in SAH patients, with and without hepatic iron-overload. Our results show that iron-overload in hepatocytes/macrophages is due to an increased expression of iron-loading receptors and CD163 signaling cascade. Increase in labile iron pool induces expression of iron-loading, oxidative-stress and inflammatory genes along with expression of CD163 and ADAM17. Increased liver iron correlated with circulatory iron, TNF-α, macrophage activation (sCD163) and peroxide-stress in CD163macrophages in patients who were iron-overloaded and died. Circulatory TNF-α and sCD163 levels were associated with poor outcome. Temporal iron/Fenton stress induced in healthy monocyte-derived-macrophage (MDM)/Tohoku-Hospital-Pediatrics-1(THP1) cells showed higher expression of iron-regulatory, inflammatory and oxidative-stress genes. These genes could be suppressed by iron-chelation. These results suggest that iron mediates inflammation through ADAM17 induction, resulting in macrophage activation and increased shedding of TNF-α and sCD163. These events could be inhibited with iron chelation or with ADAM17-blockade, postulating a therapeutic strategy for SAH patients with iron overload.
Topics: ADAM17 Protein; Adult; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Case-Control Studies; Female; Hepatitis, Alcoholic; Humans; Inflammation; Iron; Iron Overload; Liver; Macrophage Activation; Male; Middle Aged; Oxidative Stress; Prospective Studies; Receptors, Cell Surface; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 29980709
DOI: 10.1038/s41598-018-28483-x -
Immunology Jun 2022Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of immunoglobulin-type lectins that mediate protein-carbohydrate interactions via sialic acids...
Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of immunoglobulin-type lectins that mediate protein-carbohydrate interactions via sialic acids attached to glycoproteins or glycolipids. Most of the CD33-related Siglecs (CD33rSiglecs), a major subfamily of rapidly evolving Siglecs, contain a cytoplasmic signaling domain consisting of the immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) and mediate suppressive signals for lymphoid and myeloid cells. While most CD33rSiglecs are expressed by innate immune cells, such as monocytes and neutrophils, to date, the expression of Siglecs in human T cells has not been well appreciated. In this study, we found that Siglec-5, a member of the CD33rSiglecs, is expressed by most activated T cells upon antigen receptor stimulation. Functionally, Siglec-5 suppresses T cell activation. In support of these findings, we found that Siglec-5 overexpression abrogates antigen receptor induced activation of NFAT and AP-1. Furthermore, we show that GBS β-protein, a known bacterial ligand of Siglec-5, reduces the production of cytokines and cytolytic molecules by activated primary T cells in a Siglec-5 dependent manner. Our data also show that some cancer cell lines express a putative Siglec-5 ligand(s), and that the presence of soluble Siglec-5 enhances tumor-cell specific T cell activation, suggesting that some tumor cells inhibit T cell activation via Siglec-5. Together, our data demonstrate that Siglec-5 is a previously unrecognized inhibitory T cell immune checkpoint molecule and suggest that blockade of Siglec-5 could serve as a new strategy to enhance anti-tumor T cell functions.
Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Humans; Immune Checkpoint Proteins; Immunoglobulins; Lectins; Ligands; Sialic Acid Binding Immunoglobulin-like Lectins; T-Lymphocytes; Tyrosine
PubMed: 35290663
DOI: 10.1111/imm.13470 -
Journal of Hepatology Jul 2015
Topics: Animals; Antigens, Differentiation; Chemical and Drug Induced Liver Injury; JNK Mitogen-Activated Protein Kinases; Male; Metformin
PubMed: 25770661
DOI: 10.1016/j.jhep.2015.02.050 -
Cells Mar 2022Mast cells are tissue-resident cells that contribute to allergic diseases, among others, due to excessive or inappropriate cellular activation and degranulation....
Mast cells are tissue-resident cells that contribute to allergic diseases, among others, due to excessive or inappropriate cellular activation and degranulation. Therapeutic approaches to modulate mast cell activation are urgently needed. Siglec-6 is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptor selectively expressed by mast cells, making it a promising target for therapeutic intervention. However, the effects of its engagement on mast cells are poorly defined. Siglec-6 expression and endocytosis on primary human mast cells and mast cell lines were assessed by flow cytometry. mRNA expression was examined by single-cell RNAseq in esophageal tissue biopsy samples. The ability of Siglec-6 engagement or co-engagement to prevent primary mast cell activation was determined based on assessments of mediator and cytokine secretion and degranulation markers. Siglec-6 was highly expressed by all mast cells examined, and the transcript was restricted to mast cells in esophageal biopsy samples. Siglec-6 endocytosis occurred with delayed kinetics relative to the related receptor Siglec-8. Co-crosslinking of Siglec-6 with FcεRIα enhanced the inhibition of mast cell activation and diminished downstream ERK1/2 and p38 phosphorylation. The selective, stable expression and potent inhibitory capacity of Siglec-6 on human mast cells are favorable for its use as a therapeutic target in mast cell-driven diseases.
Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Line; Humans; Lectins; Mast Cells; Sialic Acid Binding Immunoglobulin-like Lectins
PubMed: 35406705
DOI: 10.3390/cells11071138