Unknown,Transcriptomics,Genomics,Proteomics

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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 p38M-NM-1 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 p38M-NM-1 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 p38M-NM-1-controlled transcripts comprising female- and male-specific gene modules, with greater p38M-NM-1 dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38M-NM-1 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

PROVIDER: E-GEOD-51707 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

<h4>Objective</h4>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.<h4>Methods</h4>Toward this end, we used experimental autoimmune ...[more]

PMID: 24027119

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Project description:How autoimmunity is initiated in Multiple Sclerosis (MS) is unknown, but both genetic and environmental factors have been implicated. Female physiology is associated with a three times higher risk of MS and the ratio of woman to men diagnosed with MS has been increasing over time, suggesting that environmental factors are interacting with female sex to initiate this disease. One MS risk factor that has been increasing that interacts with female sex is obesity. Being overweight or obese as an adolescent increases one’s risk of MS by 2-fold and this risk increases if one is female. To explore how obesity and female sex interact to control T helper autoimmunity, we conducted a proteomic screen on the serum of male and female healthy weight and obese participants that were affected or not affected by MS. We found that obese individuals, regardless of disease status, exhibited a prominent upregulation of proteins in pathways associated with the damage-associated S100 protein pathway, T helper 1 (Th1), IL-17 pathways and RIG-I/Interferon pathways and that this increase was more prominent in women. To explore the mechanisms of how female sex interacts with increased adiposity to regulate CNS autoimmunity, we modeled a diet-induced overweight (DIO) state in mice by placing animals on high fat diet for 4 weeks and then inducing experimental autoimmune encephalomyelitis (EAE), a model of MS. We found that DIO enhanced EAE severity in mice of both sexes compared to controls and this effect was more pronounced in female mice. The increased severity in the female DIO mice associated with a greater accumulation of pathogenic IFN-+IL-17+ CD4+ cells in the CNS and more severe tissue damage. Further studies of mice at steady-state revealed that DIO increased the frequency of CD44hiCD4+ T cells and enhanced the potential of naïve CD4+ T cells to produce IFN-This phenotype of higher T cell IFN-was also observed in female humans who were overweight. Furthermore, IFN-α was detected at significantly increased levels in the serum of the DIO-female compared to DIO-male or sex-matched control mice. Loss of IFN-α receptor in T cells negated the increases in Th1 inflammation and EAE severity caused by DIO in female mice. These results highlight that an overweight state may interact with female sex to selectively enhance Th1 responses and CNS autoimmunity by increasing type I and type I IFN signalling in T cells.

Project description:Highly pathogenic avian influenza viruses (HPAIV) induce severe inflammation in poultry and men. There is still an ongoing threat that these viruses may acquire the capability to freely spread as novel pandemic virus strains that may cause major morbidity and mortality. One characteristic of HPAIV infections is the induction of a cytokine burst that strongly contributes to viral pathogenicity. It has been suggested, that this cytokine overexpression is an intrinsic feature of infected cells and involves hyperinduction of p38 mitogen activated protein kinase (MAPK). Here we investigate the role of MAPK p38 signaling in the antiviral response against HPAIV in mice as well as in endothelial cells, the latter a primary source for cytokines during systemic infections. Global gene expression profiling of HPAIV infected endothelial cells in the presence of the MAP kinase p38-specific inhibitor SB202190 revealed, that inhibition of MAPK p38 leads to reduced expression of interferon (IFN) and other cytokines after A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Bratislava/79 (H7N7) infection. Furthermore, the expression of interferon stimulated genes (ISGs) after treatment with IFN or conditioned media from HPAIV infected cells was decreased when the target cells were preincubated with SB202190. Finally, promoter analysis confirmed a direct impact of p38 MAPK on the IFN-enhanceosome and ISG-promoter activity. In vivo inhibition of MAP kinase p38 greatly diminishes virus induced cytokine expression concomitant with reduced viral titers, thereby protecting mice from lethal infection. These observations show, that MAPK p38 acts on two levels of the antiviral IFN response: Initially the kinase regulates IFN induction and at a later stage MAPK p38 controls IFN signaling and thereby expression of IFN-stimulated genes. Thus, inhibition of MAP kinase p38 may be an antiviral strategy that significantly protects mice from lethal influenza via suppression of overshooting cytokine expression. HUVEC were infected with FPV in the presence or absence of a p38 MAP kinase inhibitor

Dataset Information

Sex-specific control of CNS autoimmunity by p38 MAPK signaling in myeloid cells

Publications

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

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