Biology subjects

Edelson, B.

Publications and source records attributed to Edelson, B..

3 recordsLinked to original sources

bioRxiv2026

Mycobacterium tuberculosis inactivates host oxysterols to impair macrophage cholesterol homeostasis

Host oxysterols coordinate macrophage cholesterol homeostasis and antimicrobial defense, but whether pathogens directly target oxysterol signaling is unknown. Here, we identify pathogen-mediated enzymatic oxysterol inactivation as a mechanism by which Mycobacterium tuberculosis (Mtb) subverts host cholesterol metabolism. Mtb oxidizes the endogenous oxysterols 27-hydroxycholesterol (27-HC) and 3{beta}-hydroxycholest-5-enoic acid (3{beta}-HCA) into 3-oxo-{Delta}4 metabolites. Sputum lipidomics across TB cohorts on three continents revealed an active-disease signature characterized by 27-HC depletion and accumulation of 27-hydroxycholest-4-en-3-one (27-HCO) and 3-oxocholest-4-enoic acid (3O-CA), which normalized with treatment. In infected human macrophages, Mtb 3{beta}-hydroxysteroid dehydrogenase (3{beta}-Hsd) generated 27-HCO. Unlike their parent oxysterols, 27-HCO and 3O-CA did not activate liver X receptor (LXR), and 3O-CA failed to suppress sterol regulatory element-binding protein 2 (SREBP2) target genes. Accordingly, 3{beta}-Hsd-deficient Mtb did not induce macrophage cholesterol retention, a phenotype restored by LXR antagonism. Thus, Mtb enzymatically inactivates host oxysterols, disrupting macrophage cholesterol homeostasis and generating treatment-responsive metabolic signatures in human TB.

microbiology↗

bioRxiv2022

Bystander memory-phenotype conventional CD4+ T cells exacerbating autoimmune neuroinflammation

Memory-phenotype (MP) CD4+ T cells are a substantial population of conventional T cells that exist in steady-state mice, and their immunologic functions in autoimmune disease have not yet been studied. In this work, we unveil a unique phenotype of MP CD4+ T cells by analyzing single-cell transcriptomics and T cell receptor (TCR) repertoires. We found that steady-state MP CD4+ T cells exist regardless of germ and food-antigen which are composed of heterogenous effector subpopulations. Distinct subpopulations of MP CD4+ T cells are specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells have TCR-independent effector functions. Especially, CCR6high MP CD4+ T cells are major responders to IL-1{beta} and IL-23 without MOG35-55 antigen reactivity, which gives them pathogenic-Th17 characteristics and allows them to contribute to autoimmune encephalomyelitis. We identified Bhlhe40 in CCR6high MP CD4+ T cells drives the expression of GM-CSF, contributing to CNS pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal heterogeneity of MP CD4+ T cells that can contribute to autoimmune neuroinflammation in bystander manner synergistically with antigen-specific T cells.

immunology↗

bioRxiv2020

CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity

BackgroundNatalizumab, a humanized monoclonal antibody (mAb) against 4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of 4-integrin in CD11c+ cells should curtail their migration to the CNS and ameliorate experimental autoimmune encephalomyelitis (EAE). MethodsWe generated CD11c.Cre+/-ITGA4fl/fl C57/Bl6 mice to selectively delete 4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed. Multi-parameter flow cytometry was utilized to immunophenotype leukocytes. Single-cell RNA sequencing (scRNA-seq) was used to profile individual cells. Results4-integrin expression by CD11c+ cells was significantly reduced in primary and secondary lymphoid organs in CD11c.Cre+/-ITGA4fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre+/-ITGA4fl/fl mice, during which CD11c+CD88+ cells were sequestered in the blood. Upon EAE onset, CD11c+CD88+ cells accumulated in the CNS and expressed CD317+. In adoptive transfer experiments, CD11c.Cre+/-ITGA4fl/fl mice had ameliorated clinical disease associated with diminished numbers of CNS CD11c+CD88+CD317+ cells. The transcription profile of CD11c+CD88+CD317+ cells placed them within previously defined microglia-like cells in human CSF. We show that activated, but not naive microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery. ConclusionCD11c+CD88+CD317+ cells in the CNS promote inflammatory damage. Transcriptional analysis identifies CD11c+CD88+CD317+ cells as a unique myeloid subset in human CSF. The disease-propagating effects of these cells can be antagonized using anti-CD317 mAb.

immunology↗