@article{cfdc9c39aaf3479481debfdbb18d5075,
title = "CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity",
abstract = "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 na{\"i}ve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery in mice.",
keywords = "Biomarker, CD317, EAE, Multiple sclerosis, Myeloid cells",
author = "Navid Manouchehri and Hussain, {Rehana Z.} and Cravens, {Petra D.} and Ekaterina Esaulova and Artyomov, {Maxim N.} and Edelson, {Brian T.} and Wu, {Gregory F.} and Cross, {Anne H.} and Richard Doelger and Nicolas Loof and Eagar, {Todd N.} and Forsthuber, {Thomas G.} and Laurent Calvier and Joachim Herz and Olaf St{\"u}ve",
note = "Funding Information: ACKNOWLEDGMENTS. This study was funded by Merit Review Grants federal award document number (FAIN) BX005664-01 and FAIN I01BX001674 from the US Department of Veterans Affairs, Biomedical Laboratory Research and Development (to O.S.); E.E. was supported by a Shawn Hu and Angela Zeng graduate fellowship; B.T.E. was supported by the Washington University Institute of Clinical and Translational Science Clinical and Translational Research Funding Program supported by the Foundation for Barnes-Jewish Hospital; G.F.W. was supported by the National Institute of Neurological Disorders and Stroke (Grant R01NS106289) and the National Multiple Sclerosis Society (Grant RG-1802-30253); and A.H.C. was supported in part by The Manny and Rosalyn Rosenthal and Dr. John L. Trotter Chair in Neuroimmunology of the Foundation for Barnes-Jewish Hospital. Research reported in this publication was supported by generous donations from the Lisa Novelly Fund of the John Trotter MS Center, and the Frala Osherow Fund for MS Research. Research was also supported by Washington University Institute of Clinical and Translational Sciences Grant UL1TR002345 from the National Center for Advancing Translational Sciences of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. Funding Information: Author contributions: N.M., B.T.E., G.F.W., A.H.C., T.G.F., J.H., and O.S. designed research; N.M., R.Z.H., P.D.C., E.E., M.N.A., B.T.E., G.F.W., A.H.C., R.D., T.N.E., and L.C. performed research; N.L. and L.C. contributed new reagents/analytic tools; N.M., R.Z.H., P.D.C., E.E., M.N.A., B.T.E., G.F.W., A.H.C., R.D., N.L., T.N.E., L.C., and O.S. analyzed data; and N.M., R.Z.H., T.G.F., J.H., and O.S. wrote the paper. Competing interest statement: O.S. serves on the editorial boards of Therapeutic Advances in Neurological Disorders. He has served on data monitoring committees for Gen-entech-Roche, Pfizer, and TG Therapeutics without monetary compensation. O.S. has advised EMD Serono, Celgene, Genentech, TG Therapeutics, and Genzyme. He currently receives grant support from Sanofi Genzyme and EMD Serono. G.F.W. has received honoraria for consulting for Novartis and Genentech, and received research funding from Biogen, EMD Serono, and Roche. A.H.C. has received honoraria for consulting for Biogen, Celgene, EMD Serono, Genentech, Novartis, Roche, and TG Therapeutics; she has received compensation for speaking for Genentech. This article is a PNAS Direct Submission. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). See online for related content such as Commentaries. 1To whom correspondence may be addressed. Email: olaf.stuve@utsouthwestern.edu. This article contains supporting information online at https://www.pnas.org/lookup/suppl/ doi:10.1073/pnas.2014492118/-/DCSupplemental. Published March 30, 2021. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = apr,
day = "6",
doi = "10.1073/pnas.2014492118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "14",
}