CD38+CD93+ microglia and macrophages drive neuroinflammation through glycolysis-histone lactylation axis in multiple sclerosis model mice
Neuroinflammation is a pathological hallmark of several chronic neurological diseases, including multiple sclerosis (MS), and this process is driven by the sustained activation of myeloid cells. However, the pathogenic myeloid cells subset(s) and their regulation in MS remain unclear. Here, we identify a multiple sclerosis-associated microglia and macrophage (MSMM) subset defined as CD38+CD93+ that drives MS pathogenesis.  MSMM exhibits pro-inflammatory and neurotoxic characteristics accompanied by aberrant activation of glycolysis. Mechanistically, we found that aberrant activation of glycolysis results in excessive lactate production and elevation of histone lactylation in MSMM. Histone lactylation (H3K18la and H4K12la) in turn activates the transcriptional modules of genes governing neuroinflammation and glycolysis, thereby promotes the formation of MSMM. Blockade of MSMM with anti-CD38 plus anti-CD93 neutralizing antibodies ameliorates neuroinflammation and MS-like pathologies in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inhibition of glycolysis through Ldha knock out or LDHA inhibitor decreases the number of MSMM and attenuates EAE severity. Together, these findings reveal a MS-associated pathogenic cell subset and provide potential therapeutic approaches for MS. Overall design: using single-cell RNA sequencing, spatial transcriptomics, and CUT&Tag to identify the pathogenic cell subset(s) involved in multiple sclerosispathogenesis