Deletion of the X-chromosomal gene <i>Kdm6a</i> in microglia of female mice ameliorates neuroinflammation and restores translatome profiles

Women are more susceptible to multiple sclerosis (MS) than men, with a reported incidence ratio of ~3:1. <i>Kdm6a</i> is an X-chromosomal gene that escapes X inactivation, leading to higher expression of the histone demethylase KDM6A in females compared with males. Here, we focused on the role of <i>Kdm6a</i> in microglia in MS because this cell type plays a key role in the neuropathology of MS. <i>Kdm6a</i> was selectively deleted from microglia in experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. Deletion of <i>Kdm6a</i> in microglia ameliorated pathology, reduced the expression of disease-associated markers, increased the expression of resting microglial markers, and reversed other translatome changes in spinal cord tissues of female EAE mice. Deletion of <i>Kdm6a</i> in microglia had only very minor effects on EAE in male mice. The diabetes medicine metformin, which also blocks KDM6A's histone demethylase activity, ameliorated EAE in females, but not males, and normalized translatome profiles in microglia. CUT&RUN and sequencing analysis of microglial nuclei identified genes bound by KDM6A. When combined with translatomic analysis, this revealed correspondence between KDM6A protein binding and gene expression changes. Transcriptomic analysis of human microglia confirmed the higher expression of <i>KDM6A</i> in women compared with men and revealed that more microglial genes were dysregulated in women than in men with MS. Our results suggest that <i>KDM6A</i> might contribute to sex differences in susceptibility to MS.