RRC ID 27779
Author Krementsov DN, Noubade R, Dragon JA, Otsu K, Rincon M, Teuscher C.
Title Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells.
Journal Ann Neurol
Abstract OBJECTIVE:Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. Investigators have described p38 mitogen-activated protein kinase (MAPK) as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored.
METHODS:Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses.
RESULTS:Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38α signaling in macrophages/myeloid cells, but not T cells or dendritic cells, mediated this sexual dimorphism, which was dependent on the presence of adult sex hormones. Analysis of CNS inflammatory infiltrates showed that female but not male mice lacking p38α in myeloid cells exhibited reduced immune cell activation compared with controls, whereas peripheral T-cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38α-controlled transcripts comprising female- and male-specific gene modules, with greater p38α dependence of proinflammatory gene expression in females.
INTERPRETATION:Our findings demonstrate a key role for p38α in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease-modifying therapies for MS.
Volume 75(1)
Pages 50-66
Published 2014-1-1
DOI 10.1002/ana.24020
PMID 24027119
PMC PMC3945470
MeSH Animals Autoimmunity / physiology* Cells, Cultured Encephalomyelitis, Autoimmune, Experimental / enzymology* Encephalomyelitis, Autoimmune, Experimental / immunology Enzyme Activation / physiology Female MAP Kinase Signaling System / physiology* Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mitogen-Activated Protein Kinase 14 / immunology Mitogen-Activated Protein Kinase 14 / metabolism* Myeloid Cells / enzymology* Myeloid Cells / immunology Sex Characteristics* p38 Mitogen-Activated Protein Kinases / immunology p38 Mitogen-Activated Protein Kinases / metabolism
IF 9.037
Times Cited 27
Mice RBRC02192