p38 MAP kinase signaling in microglia plays a sex-specific protective role in CNS autoimmunity and regulates microglial transcriptional states

Abstract Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. MS three times more common in women, yet severe men. The mechanisms underlying these sex differences remain largely unknown. initiated by autoreactive T cells, but CNS-infiltrating myeloid cells are key effector driving pathology. role CNS-resident microglial less clear. We have previously shown that genetic ablation p38α MAP kinase broadly lineage protective model MS, experimental encephalomyelitis (EAE), only females, and not males. Here, we sought to define responsible, using approaches bone marrow chimeras ablate peripheral or both. Deletion both cell types recapitulated previous difference, with reduced EAE severity females. Unexpectedly, deletion periphery was sexes. In contrast, microglia exacerbated males only, revealing opposing roles vs. periphery. Single-cell RNAseq revealed a diversity states, connected distinct convergent transcriptional trajectories. Microglial deficiency resulted enhanced transition from homeostatic disease-associated microglia, downregulation regulatory genes such as Atf3, Rgs1, Btg2, upregulation inflammatory Cd74, Trem2, MHC class I II. These results reveal p38α-dependent male-specific molecular pathway CNS autoimmunity, suggesting autoimmunity females may be driven cellular pathways.