CD11c
| Autor: | Navid, Manouchehri, Rehana Z, Hussain, Petra D, Cravens, Ekaterina, Esaulova, Maxim N, Artyomov, Brian T, Edelson, Gregory F, Wu, Anne H, Cross, Richard, Doelger, Nicolas, Loof, Todd N, Eagar, Thomas G, Forsthuber, Laurent, Calvier, Joachim, Herz, Olaf, Stüve |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance The bone marrow-derived CD11c+CD88+CD317+ myeloid cells within the central nervous system are associated with clinical experimental autoimmune encephalomyelitis. Transcriptional analyses identify ITGAX- (CD11c), C5AR1- (CD88), and BST2- (CD317) expressing cells as a distinct myeloid subset in human cerebrospinal fluid. The disease-propagating effects of these cells in experimental autoimmune encephalomyelitis can be effectively antagonized using anti-CD317 monoclonal antibody therapy. Natalizumab, a humanized monoclonal antibody (mAb) against α4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of α4-integrin in CD11c+ cells should curtail their migration to the central nervous system (CNS) and ameliorate experimental autoimmune encephalomyelitis (EAE). We generated CD11c.Cre+/−ITGA4fl/fl C57BL/6 mice to selectively delete α4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed and compared with WT controls. Multiparameter flow cytometry was utilized to immunophenotype leukocyte subsets. Single-cell RNA sequencing was used to profile individual cells. α4-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 clinical EAE onset, CD11c+CD88+ cells appeared in the CNS and expressed CD317+. In adoptive transfer experiments, CD11c.Cre+/−ITGA4fl/fl mice had ameliorated clinical disease phenotype associated with significantly diminished numbers of CNS CD11c+CD88+CD317+ cells. In human cerebrospinal fluid from subjects with neuroinflammation, microglia-like cells display coincident expression of ITGAX (CD11c), C5AR1 (CD88), and BST2 (CD317). In mice, we show that only activated, but not naïve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery in mice. |
| Databáze: | OpenAIRE |
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