P38 MAP kinase signaling in microglia plays a sex-specific protective role in CNS autoimmunity

Abstract

Abstract Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, representing the leading cause of non-traumatic neurologic disease in young adults. This disease is 3 times more common in women, but the underlying mechanisms remain unknown. MS is initiated by autoreactive T helper cells, but CNS-infiltrating inflammatory myeloid cells are the main effector cells driving disease pathology. The role of CNS-resident macrophage-like microglial cells is unclear. We have previously shown that genetic ablation of p38α MAP kinase (p38) in the myeloid lineage is protective in the autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE). Strikingly, protection was seen in female mice, and not males. Here, we sought to precisely define the mechanisms responsible. To this end, we used multiple genetic approaches and bone marrow chimeras to ablate p38 in microglial cells, peripheral myeloid cells, or both. Deletion of p38 in both cell types recapitulated the previous sex difference, with reduced EAE severity in females. Unexpectedly, deletion of p38 in the periphery was protective in both sexes, while deletion of p38 in microglia exacerbated EAE only in males. Transcriptional profiling of microglia isolated from the CNS at peak of EAE revealed male-specific p38-dependent transcriptional modules with anti-inflammatory/tissue reparatory functionality. Taken together, these results reveal the presence of a p38-dependent male-specific molecular pathway in microglia that is protective in CNS autoimmunity, suggesting that autoimmunity in males and females may be driven by distinct cellular and molecular pathways, thus informing the design of novel future sex-specific therapeutic approaches.