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

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 Overall design: WT vs. p38alphaCKO macrophages, male vs. female

研究目标：多发性硬化症（Multiple sclerosis, MS）是一种中枢神经系统（central nervous system, CNS）慢性炎症性脱髓鞘疾病，其全球发病率呈上升趋势，且该增长趋势主要由女性复发缓解型病例驱动。p38丝裂原活化蛋白激酶（p38 MAP kinase, MAPK）已被证实是自身免疫炎症反应的关键调控因子，但其在多发性硬化或其相关疾病模型中的性别差异作用尚未被阐明。
研究方法：为此，本研究采用多发性硬化的经典动物模型——实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE），联合使用p38 MAPK活性的药物学抑制与遗传学抑制手段，并开展转录组学分析。
研究结果：p38 MAPK的药物学抑制可选择性改善雌性小鼠的EAE症状。条件性敲除实验证实，巨噬细胞/髓系细胞中的p38α信号通路（而非T细胞或树突状细胞）可重现该性别差异。对中枢神经系统炎症浸润灶的分析显示，与对照组相比，髓系细胞缺失p38α的雌性小鼠免疫细胞活化程度显著降低，而两性的外周T细胞致敏均未受影响。对髓系细胞的转录组学分析表明，p38α调控的转录本存在性别特异性差异，包含雌性特异性与雄性特异性基因模块，且雌性促炎基因的表达对p38α的依赖性更强。
研究解读：本研究结果证实了髓系细胞中p38α在中枢神经系统自身免疫中的关键作用，并揭示了疾病发病机制中性别差异背后的重要分子机制。综上，本研究结果表明p38 MAPK信号通路可作为多发性硬化亟需的疾病修饰治疗的新型靶点。
实验总体设计：野生型（WT）与p38α条件性敲除（p38alphaCKO）巨噬细胞，分为雄性与雌性两组。