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| Status |
Public on Oct 29, 2013 |
| Title |
Sex-specific control of CNS autoimmunity by p38 MAPK signaling in myeloid cells |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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
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| Overall design |
WT vs. p38alphaCKO macrophages, male vs. female
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| Contributor(s) |
Krementsov DN, Noubade R, Dragon JA, Otsu K, Rincon M, Teuscher C |
| Citation(s) |
24027119 |
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| Submission date |
Oct 25, 2013 |
| Last update date |
Feb 21, 2018 |
| Contact name |
Dimitry Krementsov |
| E-mail(s) |
dkrement@uvm.edu
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| Organization name |
University of Vermont
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| Department |
BHSC
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| Street address |
312C Rowell bldg, 106 Carrigan drive
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| City |
89 Beaumont ave |
| State/province |
VT |
| ZIP/Postal code |
05405 |
| Country |
USA |
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| Platforms (1) |
| GPL16570 |
[MoGene-2_0-st] Affymetrix Mouse Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA225461 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE51707_RAW.tar |
109.6 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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