CD36 mediates transfer of thymic cell-surface antigens to promote regulatory T cell receptor repertoire development and allo-tolerance
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ABSTRACT:
PROVIDER: PRJEB25804 | ENA |
REPOSITORIES: ENA
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Project description:Monocytes and macrophages as components of innate immunity are critical for both homeostasis and inflammation. The scavenger receptor CD36, highly expressed in macrophages, promotes immunological responses mediated by recognition of molecular patterns on pathogens or endogenous ligands on apoptotic cells. CD36 mediated lipid uptake also allows metabolic adaptations that influence macrophage phenotype and polarization. CD36 binds diverse lipids including fatty acids and various lipoproteins, which could exert differential effects on macrophage conversion. Previous studies reported opposite outcomes due to CD36-mediated lipid uptake; macrophages converted to either an inflammatory or an alternatively activated phenotype. To determine the role of this receptor in vivo in the presence of physiological lipid sources, we created macrophage-specific CD36 knockout mice. Using zymosan-induced peritonitis to activate immune cells, we show through single cell RNA sequencing analysis that a broad variety of resident and infiltrated immune cells are present in the peritoneum 72h after the initial stimulus. CD36 deficiency did not affect the numbers of cells during the infiltration and resolution phases, but CD36 deficiency altered the macrophage transcriptome. Pathways related to innate immunity, antigen presentation and oxidative phosphorylation were upregulated in macrophages with CD36 deficiency, whereas those related to efferocytosis, adaptive immunity and B cell activation were downregulated. Despite these gene changes, neither immunoglobulin production nor peritoneal efferocytosis was altered by macrophage CD36 deficiency, nor were there changes in the numbers of circulating white blood cells. Thus, CD36 deficiency does not reduce the inflammatory phenotype of induced peritoneal macrophages.
2024-05-31 | GSE210795 | GEO
Project description:Hypoxia is a hallmark of renal ischemia reperfusion injury (IRI) and serves as an essential regulator of innate immune responses during this process, although the mechanisms of this regulation remain unclear. Here, we show that dendritic cell (DC)-specific genetic ablation of hypoxia-inducible factor (HIF) 2α, a transcription factor induced by oxygen shortage, leads to hyperactivation of natural killer T cells (NKTs), ultimately exacerbating renal IRI in mice. HIF-2α deficiency in DCs triggers IFN-γ and IL-4 production in NKTs, along with upregulation of type I interferon (IFN) and chemokine responses critical for NKT activation. Mechanistically, loss of HIF-2α in DCs promotes their expression of CD36, a scavenger receptor for lipid uptake, resulting in increased lipid accumulation. Furthermore, HIF-2α binds directly to a reverse hypoxia-responsive element (rHRE) in the CD36 promoter, supporting its transcriptional regulation of CD36. Importantly, CD36 blockade by sulfo-N-succinimidyl oleate (SSO), reduces NKT activation and abolishes the exacerbation of renal IRI in mice with DC-specific HIF-2α knockout. Taken together, our study reveals a previously unrecognized role of a HIF-2α-CD36 regulatory axis in rewiring DC lipid metabolism under IRI-associated hypoxia, and suggests a potential therapeutic target to resolve long-standing obstacles in clinical treatment of this severe complication.
2022-09-23 | GSE199875 | GEO
Project description:Tyrosine kinase inhibitors (TKIs) are highly effective for treatment of chronic myeloid leukemia (CML), but very few patients are cured. Major drawbacks with TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon TKI cessation. Here, we performed RNA-sequencing of flow-sorted primitive (CD34+CD38low) and progenitor (CD34+CD38+) chronic phase CML cells and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor (LEPR) by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting antibodies, we show that the CD36 positive cells can be targeted and killed by antibody dependent cellular cytotoxicity (ADCC). In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitivity that can be effectively targeted by ADCC using an anti-CD36 antibody.
| EGAS00001002421 | EGA
Project description:The identification of molecules for apoptotic cells (AC) uptake by dendritic cells (DCs) and induction of T cell immunity is a major challenge in immunology.<br>DCs generated from monocytes in the presence of IFN-alpha (IFN-alpha-DCs) are competent in taking up ACs and inducing a strong T cell immunity. Capture of allogenetic apoptotic lymphocytes (APO-allo-PBLs) was associated with subcellular rearrangements of MHC class I/II molecules, subsequent cross-priming of auologous CD8+ T cells and CD4+ T cell activation. All these events were inhibited by the Scavenger Receptor (SR) LOX-1 protein, whose expression was up-regulated in IFN-alpha DCs. The results unravel a novel natural IFN-alpha-mediated pathway by which a defined SR molecule regulates AC uptake by DCs and subsequent induction of T cell immunity.
2010-01-08 | E-MEXP-2000 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: The scavenger receptor CD36 has versatile immuno-metabolic actions. CD36 is abundantly expressed in the small intestinal epithelium but its impact on gut homeostasis is unknown. METHODS: Wild type (WT) and CD36-null (CD36KO) mice were fed a chow diet and small intestinal morphology assessed by immunohistochemistry and electron microscopy (EM). Inflammation was evaluated from neutrophil infiltration, expression of cytokines and toll-like receptors. Barrier integrity was determined using FITC-dextran and circulating lipopolysaccharide (LPS). Enterocyte (Ent-CD36KO) and endothelial (EC-CD36KO) CD36 null mice were generated to test contribution of epithelial versus endothelial CD36 to the intestinal phenotype. RESULTS: The small intestine of CD36KO mice fed a chow diet showed abnormal remodeling of the extracellular matrix (ECM) with altered expression of ECM and junction proteins. Hypertrophy of cell junctions and basement membranes was observed by EM. The CD36KO intestines displayed neutrophil infiltration, inflammation and compromised barrier function. Systemic leukocytosis and neutrophilia were present in CD36KO mice and there was 80% reduction of anti-inflammatory Ly6Clow monocytes important for ECM regulation and tissue repair. Bone marrow transplants supported primary contribution of tissue injury in initiation of inflammation. Studies with Ent-CD36KO mice did not support a major contribution of enterocyte CD36 while endothelial CD36 deficiency associated with neutrophil infiltration, aberrant expression of tight junctions and inflammation in the small intestine. CONCLUSION: CD36 is important for maintenance of barrier function in the small intestine. CD36 deletion causes ECM remodeling with collagen accumulation, depletion of the Ly6Clow monocyte subset and chronic inflammation. Endothelial but not enterocyte CD36 loss is a significant contributor to the spontaneous inflammation.
2016-10-01 | GSE73569 | GEO
Project description:The goal of our study is to determine whether Atg16L1 deficiency leads to differences in the transcriptional profile of CD11c+ Dendritic Cells, ultimately leading to an increased inflammatory phenotype. CD11c+ cell sorted splenic DCs were isolated from 8 week old WT and Atg16L1 hypomorphic mice from spleens of allo-HSCT recipients on day 7 were placed directly into TRIzol LS (Invitrogen). mRNA was isolated, amplified, and hybridized to an Affymetrix GeneChip (MOE430A).
2014-09-19 | E-GEOD-61560 | biostudies-arrayexpress
Project description:The presentation of self-antigens in the thymus by medullary thymic epithelial cells (mTECs) and dendritic cells (DCs) is crucial for the establishment of central tolerance. While mTECs produce and present self-antigens in an autonomous manner, DCs acquire them from mTECs by Cooperative Antigen Transfer (CAT). Although CAT represents a key process of central tolerance, molecular determinants which drive CAT are largely unknown. To reveal these determinants, we compared the transcriptomes of CAT-experienced and CAT-inexperienced DCs via scRNAseq. Specifically, we sequenced TdTOMATO+ and TdTOMATO– CD11c+ and CD11b+ cells from the thymus of Foxn1CreR26TdTOMATO mice. In this model, fluorescent TdTOMATO protein is exclusively produced by thymic epithelium, thus TdTOMATO expression in DCs (CD11c+ and CD11b+ cells) mark their previous experience of CAT. Using this approach we unraveled several candidate determinants of CAT. We focused on the gene determinant, Cldn1, encoding the tight junction protein Claudin 1, that was found to be highly expressed among the CAT-experienced type 1 lineage DCs. We performed further experiments that confirmed its role in driving CAT. In addition, this scRNAseq approach allowed us to redefine the heterogeneity and maturation states of thymic DCs.
2024-07-31 | E-MTAB-14319 | biostudies-arrayexpress
Project description:Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multi-ligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that CD36-mediated FA transport across ECs rate-limits tissue FA uptake, and its loss leads to metabolic effects in parenchymal cells.
2018-06-28 | GSE116350 | GEO
Project description:Adipose-derived MSCs (AMSC) are currently utilized in clinical trials for various diseases including osteoarthritis, amyotrophic lateral sclerosis, and multiple system atrophy. Whilst AMSCs may be defined by the surface expression of classical markers including CD44, CD90, CD105, and absence of CD45, these cells may exhbit donor-to-donor differences in differentiation potential. In this study we evaluated the expression of CD36 amongst AMSCs and utilized magnetic cell sorting to enrich for CD36+ cells. Whole transcriptome RNA-sequencing was performed on unsorted, CD36+ enriched, and CD36+ depleted cells to determine gene expression difference between these populations of cells. CD36 sorted or unsorted cells were then plated and maintained in growth medium. Cells were expanded for 2 passages and passage 8 cells were plated for RNA-sequencing analysis. Trizol reagent was used to harvest cells when they were proliferating cells (~80%) or 100% confluent cells.
2021-11-28 | GSE189525 | GEO