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The Journal of Clinical Investigation Mar 2018Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously...
Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.
Topics: Adult; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Atherosclerosis; Coronary Disease; Coronary Vessels; Disease Progression; Female; Hemoglobins; Humans; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Middle Aged; Myocardial Infarction; Neovascularization, Pathologic; Oxidative Stress; Permeability; Phenotype; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Signal Transduction
PubMed: 29457790
DOI: 10.1172/JCI93025 -
Journal of Virology May 2023The porcine reproductive and respiratory syndrome viruses (PRRSV) led to a global panzootic and huge economical losses to the pork industry. PRRSV targets the scavenger...
The porcine reproductive and respiratory syndrome viruses (PRRSV) led to a global panzootic and huge economical losses to the pork industry. PRRSV targets the scavenger receptor CD163 for productive infection. However, currently no effective treatment is available to control the spread of this disease. Using bimolecular fluorescence complementation (BiFC) assays, we screened a set of small molecules potentially targeting the scavenger receptor cysteine-rich domain 5 (SRCR5) of CD163. We found that the assay examining protein-protein interactions (PPI) between PRRSV glycoprotein 4 (GP4) and the CD163-SRCR5 domain mainly identifies compounds that potently inhibit PRRSV infection, while examining the PPI between PRRSV-GP2a and the SRCR5 domain maximized the identification of positive compounds, including additional ones with various antiviral capabilities. These positive compounds significantly inhibited both types 1 and 2 PRRSV infection of porcine alveolar macrophages. We confirmed that the highly active compounds physically bind to the CD163-SRCR5 protein, with dissociation constant () values ranging from 28 to 39 μM. Structure-activity-relationship (SAR) analysis revealed that although both the 3-(morpholinosulfonyl)anilino and benzenesulfonamide moieties in these compounds are critical for the potency to inhibit PRRSV infection, the morpholinosulfonyl group can be replaced by chlorine substituents without significant loss of antiviral potency. Our study established a system for throughput screening of natural or synthetic compounds highly effective on blocking of PRRSV infection and shed light on further SAR modification of these compounds. Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the swine industry worldwide. Current vaccines cannot provide cross protection against different strains, and there are no effective treatments available to hamper the spread of this disease. In this study, we identified a group of new small molecules that can inhibit the PRRSV interaction with its specific receptor CD163 and dramatically block the infection of both types 1 and type 2 PRRSVs to host cells. We also demonstrated the physical association of these compounds with the SRCR5 domain of CD163. In addition, molecular docking and structure-activity relationship analyses provided new insights for the CD163/PRRSV glycoprotein interaction and further improvement of these compounds against PRRSV infection.
Topics: Swine; Animals; Porcine respiratory and reproductive syndrome virus; Porcine Reproductive and Respiratory Syndrome; Molecular Docking Simulation; Antigens, Differentiation, Myelomonocytic; Receptors, Scavenger
PubMed: 37133376
DOI: 10.1128/jvi.00054-23 -
Journal of Immunological Methods Sep 2014Effects of exosomes present in human plasma on immune cells have not been examined in detail. Immunological studies with plasma-derived exosomes require their isolation... (Clinical Trial)
Clinical Trial
Effects of exosomes present in human plasma on immune cells have not been examined in detail. Immunological studies with plasma-derived exosomes require their isolation by procedures involving ultracentrifugation. These procedures were largely developed using supernatants of cultured cells. To test biologic activities of plasma-derived exosomes, methods are necessary that ensure adequate recovery of exosome fractions free of contaminating larger vesicles, cell fragments and protein/nucleic acid aggregates. Here, an optimized method for exosome isolation from human plasma/serum specimens of normal controls (NC) or cancer patients and its advantages and pitfalls are described. To remove undesirable plasma-contaminating components, ultrafiltration of differentially-centrifuged plasma/serum followed by size-exclusion chromatography prior to ultracentrifugation facilitated the removal of contaminants. Plasma or serum was equally acceptable as a source of exosomes based on the recovered protein levels (in μg protein/mL plasma) and TEM image quality. Centrifugation on sucrose density gradients led to large exosome losses. Fresh plasma was the best source of morphologically-intact exosomes, while the use of frozen/thawed plasma decreased exosome purity but not their biologic activity. Treatments of frozen plasma with DNAse, RNAse or hyaluronidase did not improve exosome purity and are not recommended. Cancer patients' plasma consistently yielded more isolated exosomes than did NCs' plasma. Cancer patients' exosomes also mediated higher immune suppression as evidenced by decreased CD69 expression on responder CD4+ T effector cells. Thus, the described procedure yields biologically-active, morphologically-intact exosomes that have reasonably good purity without large protein losses and can be used for immunological, biomarker and other studies.
Topics: Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Blood Buffy Coat; CD4-Positive T-Lymphocytes; Cells, Cultured; Deoxyribonucleases; Exosomes; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronoglucosaminidase; Lectins, C-Type; Male; Microscopy, Electron, Transmission; Neoplasm Proteins; Neoplasms; Ribonucleases
PubMed: 24952243
DOI: 10.1016/j.jim.2014.06.007 -
Genes Jan 2021Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (). Originally described as a component of the cornified... (Review)
Review
Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (). Originally described as a component of the cornified envelope, the function of stratified epithelia-expressed is unknown. Both the lack of knowledge about the gene role under physiological conditions and the emerging link of to various human diseases, including cancer, attract research interest. The association of expression with poor prognosis of patients suffering from oesophageal carcinoma, glioblastoma multiforme, and myelodysplastic syndromes suggests that may play a role in human tumourigenesis. Three isoforms code for the secreted proteins with putative function as signalling molecules, yet with poorly described effects. In this first review about , we summarised the current knowledge accumulated since its original description, and we discuss the potential mechanisms and roles of in both physiology and pathology.
Topics: Antigens, Differentiation; Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Neoplasms
PubMed: 33477529
DOI: 10.3390/genes12010108 -
Nature Communications Feb 2021Changes in glycosylation during tumour progression are a key hallmark of cancer. One of the glycan moieties generally overexpressed in cancer are sialic acids, which can...
Changes in glycosylation during tumour progression are a key hallmark of cancer. One of the glycan moieties generally overexpressed in cancer are sialic acids, which can induce immunomodulatory properties via binding to Siglec receptors. We here show that Pancreatic Ductal Adenocarcinoma (PDAC) tumour cells present an increased sialylation that can be recognized by Siglec-7 and Siglec-9 on myeloid cells. We identified the expression of the α2,3 sialyltransferases ST3GAL1 and ST3GAL4 as main contributor to the synthesis of ligands for Siglec-7 and Siglec-9 in tumour cells. Analysing the myeloid composition in PDAC, using single cell and bulk transcriptomics data, we identified monocyte-derived macrophages as contributors to the poor clinical outcome. Tumour-derived sialic acids dictate monocyte to macrophage differentiation via signalling through Siglec-7 and Siglec-9. Moreover, triggering of Siglec-9 in macrophages reduce inflammatory programmes, while increasing PD-L1 and IL-10 expression, illustrating that sialic acids modulate different myeloid cells. This work highlights a critical role for sialylated glycans in controlling immune suppression and provides new potential targets for cancer immunotherapy in PDAC.
Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Differentiation; Cell Line, Tumor; Clustered Regularly Interspaced Short Palindromic Repeats; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Lectins; Macrophages; Monocytes; Pancreas; Pancreatic Neoplasms; Phosphorylation; Sialic Acid Binding Immunoglobulin-like Lectins; Sialic Acids
PubMed: 33627655
DOI: 10.1038/s41467-021-21550-4 -
Reviews in Endocrine & Metabolic... Jun 2022TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a member of the TNF superfamily that controls a multitude of cellular events including proliferation,... (Review)
Review
TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a member of the TNF superfamily that controls a multitude of cellular events including proliferation, migration, differentiation, apoptosis, angiogenesis, and inflammation. TWEAK control of these events is via an expanding list of intracellular signalling pathways which include NF-κB, ERK/MAPK, Notch, EGFR and AP-1. Two receptors have been identified for TWEAK - Fn14, which targets the membrane bound form of TWEAK, and CD163, which scavenges the soluble form of TWEAK. TWEAK appears to elicit specific events based on the receptor to which it binds, tissue type in which it is expressed, specific extrinsic conditions, and the presence of other cytokines. TWEAK signalling is protective in healthy tissues, but in chronic inflammatory states become detrimental to the tissue. Consistent data show a role for the TWEAK/FN14/CD163 axis in metabolic disease, chronic autoimmune diseases, and acute ischaemic stroke. Low circulating concentrations of soluble TWEAK are predictive of poor cardiovascular outcomes in those with and without diabetes. This review details the current understanding of the TWEAK/Fn14/CD163 axis as one of the chief regulators of immune signalling and its cell-specific role in metabolic disease development and progression.
Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Brain Ischemia; Cytokine TWEAK; Humans; Inflammation; Metabolic Diseases; Receptors, Cell Surface; Receptors, Tumor Necrosis Factor; Stroke; TWEAK Receptor; Tumor Necrosis Factors
PubMed: 34542797
DOI: 10.1007/s11154-021-09688-4 -
Nature Immunology Oct 2014The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the...
The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2-dependent influx of Ly6C(hi) monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool.
Topics: Animals; Animals, Newborn; Antigens, Differentiation; Antigens, Ly; Bone Marrow Transplantation; CD11b Antigen; CX3C Chemokine Receptor 1; Cell Differentiation; Cell Proliferation; Flow Cytometry; Gene Expression; Intestinal Mucosa; Intestines; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Immunological; Monocytes; Parabiosis; Receptors, CCR2; Receptors, Chemokine; Reverse Transcriptase Polymerase Chain Reaction; Time Factors
PubMed: 25151491
DOI: 10.1038/ni.2967 -
Scientific Reports Oct 2016Renal failure is one of the most important social problems for its incurability and high costs for patients' health care. Through clarification of the underlying...
Renal failure is one of the most important social problems for its incurability and high costs for patients' health care. Through clarification of the underlying mechanism for the high susceptibility of cats to renal disease, we here demonstrates that the effective dissociation of serum AIM protein from IgM is necessary for the recovery from acute kidney injury (AKI). In cats, the AIM-IgM binding affinity is 1000-fold higher than that in mice, which is caused by the unique positively-charged amino-acid cluster present in feline AIM. Hence, feline AIM does not dissociate from IgM during AKI, abolishing its translocation into urine. This results in inefficient clearance of lumen-obstructing necrotic cell debris at proximal tubules, thereby impairing AKI recovery. Accordingly, mice whose AIM is replaced by feline AIM exhibit higher mortality by AKI than in wild-type mice. Recombinant AIM administration into the mice improves their renal function and survival. As insufficient recovery from AKI predisposes patients to chronic, end-stage renal disease, feline AIM may be involved crucially in the high mortality of cats due to renal disease. Our findings could be the basis of the development of novel AKI therapies targeting AIM-IgM dissociation, and may support renal function in cats and prolong their lives.
Topics: Amino Acid Sequence; Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Cat Diseases; Cats; Disease Susceptibility; Kidney Diseases; Lectins, C-Type; Sequence Homology, Amino Acid
PubMed: 27731392
DOI: 10.1038/srep35251 -
Frontiers in Immunology 2022In recent years, a set of immune receptors that interact with members of the nectin/nectin-like (necl) family has garnered significant attention as possible points of... (Review)
Review
In recent years, a set of immune receptors that interact with members of the nectin/nectin-like (necl) family has garnered significant attention as possible points of manipulation in cancer. Central to this axis, CD226, TIGIT, and CD96 represent ligand (CD155)-competitive co-stimulatory/inhibitory receptors, analogous to the CTLA-4/B7/CD28 tripartite. The identification of PVRIG (CD112R) and CD112 has introduced complexity and enabled additional nodes of therapeutic intervention. By virtue of the clinical progression of TIGIT antagonists and emergence of novel CD96- and PVRIG-based approaches, our overall understanding of the 'CD226 axis' in cancer immunotherapy is starting to take shape. However, several questions remain regarding the unique characteristics of, and mechanistic interplay between, each receptor-ligand pair. This review provides an overview of the CD226 axis in the context of cancer, with a focus on the status of immunotherapeutic strategies (TIGIT, CD96, and PVRIG) and their underlying biology (i.e., / interactions). We also integrate our emerging knowledge of the immune populations involved, key considerations for Fc gamma (γ) receptor biology in therapeutic activity, and a snapshot of the rapidly evolving clinical landscape.
Topics: Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Humans; Immunotherapy; Ligands; Nectins; Neoplasms; Receptors, Immunologic
PubMed: 35812451
DOI: 10.3389/fimmu.2022.914406 -
International Journal of Molecular... Dec 2023Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new... (Review)
Review
Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new cancer immunotherapies (e.g., CTLA-4 and PD-1). CD6 is a signal-transducing transmembrane receptor, mainly expressed by all T cells and some B and NK cell subsets, whose endogenous ligands (CD166/ALCAM, CD318/CDCP-1, Galectins 1 and 3) are overexpressed by malignant cells of different lineages. This places CD6 as a potential target for novel therapies against haematological and non-haematological malignancies. Recent experimental evidence for the role of CD6 in cancer immunotherapies is summarised in this review, dealing with diverse and innovative strategies from the classical use of monoclonal antibodies to soluble recombinant decoys or the adoptive transfer of immune cells engineered with chimeric antigen receptors.
Topics: Activated-Leukocyte Cell Adhesion Molecule; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Immunotherapy; Neoplasms; T-Lymphocytes
PubMed: 38139340
DOI: 10.3390/ijms242417510