期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：14
页码：1
DOI：10.1073/pnas.2014492118
出版社：The National Academy of Sciences of the United States of America
摘要：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 /− ITGA4 fl/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 /− ITGA4 fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre /− ITGA4 fl/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 /− ITGA4 fl/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.
