Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells
Dimitry N. Krementsov PhD
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT
Search for more papers by this authorRajkumar Noubade PhD
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT
Genentech, Inc, South San Francisco, CA
Search for more papers by this authorJulie A. Dragon PhD
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT
Search for more papers by this authorKinya Otsu MD, PhD
Cardiovascular Division, King's College London, London, UK
Search for more papers by this authorMercedes Rincon PhD
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT
Search for more papers by this authorCorresponding Author
Cory Teuscher PhD
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT
Address correspondence to Dr Teuscher, Immunobiology Program, C331 Given Medical Building, University of Vermont, Burlington, VT 05405. E-mail: [email protected]Search for more papers by this authorDimitry N. Krementsov PhD
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT
Search for more papers by this authorRajkumar Noubade PhD
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT
Genentech, Inc, South San Francisco, CA
Search for more papers by this authorJulie A. Dragon PhD
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT
Search for more papers by this authorKinya Otsu MD, PhD
Cardiovascular Division, King's College London, London, UK
Search for more papers by this authorMercedes Rincon PhD
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT
Search for more papers by this authorCorresponding Author
Cory Teuscher PhD
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT
Address correspondence to Dr Teuscher, Immunobiology Program, C331 Given Medical Building, University of Vermont, Burlington, VT 05405. E-mail: [email protected]Search for more papers by this authorAbstract
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. Ann Neurol 2014;75:50–66
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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