Sex‐specific control of central nervous system autoimmunity by p38 mitogen‐activated protein kinase signaling in myeloid cells

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 relapsingremitting disease in females. p38 MAP kinase (MAPK) has been described 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, recapitulated this sexual dimorphism. 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, while 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 pro-inflammatory 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.

Exacerbation of autoimmune neuroinflammation by dietary sodium is genetically controlled and sex specific

“…Augmented induction of T h 17 cells by high sodium has been shown to be dependent on a signaling pathway involving serum glucocorticoid kinase 1 and p38α MAPK in T cells, although the in vivo cell‐specific requirement for p38α for EAE exacerbation by dietary sodium has not been shown (4). Moreover, using cell type‐specific genetic ablation of p38α, we have previously shown that p38α plays cell‐specific roles in EAE independent of diet (24). Hence, we used the same approach to delineate the cell type‐specific contribution of p38 MAPK signaling to sodium‐mediated exacerbation of EAE.…”

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection

“…Data were normalized to the expression of the housekeeping gene, B2m. SYBR Green-based qRT-PCR was performed as described previously (65).…”

(Putative) sex differences in neuroimmune modulation of memory

“…Downstream of cytokine activation, second messenger signaling and transcription factors also show sexspecific activity. For example, p38MAPK mediates symptoms only in females in a mouse model of multiple sclerosis (Krementsov et al, 2014), and lipocalin-2 is required for increasing body temperature after LPS in females but not males (Hamzic et al, 2013). Furthermore, COX-2 is required for hippocampal memory only in females (Guzm an et al, 2009).…”

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