Transcriptomics

Dataset Information

3

Sex-specific control of CNS autoimmunity by p38 MAPK 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 relapsing-remitting 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 WT vs. p38alphaCKO macrophages, male vs. female

ORGANISM(S): Mus musculus  

SUBMITTER: Dimitry Krementsov   J A Dragon  M Rincon  D N Krementsov  C Teuscher  K Otsu  R Noubade 

PROVIDER: E-GEOD-51707 | ArrayExpress | 2013-10-29

SECONDARY ACCESSION(S): GSE51707PRJNA225461

REPOSITORIES: GEO, ArrayExpress

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Publications

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

Krementsov Dimitry N DN   Noubade Rajkumar R   Dragon Julie A JA   Otsu Kinya K   Rincon Mercedes M   Teuscher Cory C  

Annals of neurology 20140101 1


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 encephalomyelit  ...[more]

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