Microglia regulate myelin clearance and cholesterol metabolism after demyelination via interferon regulatory factor 5

Interferon regulatory factor 5 (IRF5) is a transcription factor that plays a role in orchestrating innate immune responses, particularly in response to viral infections. Notably, IRF5 has been identified as a microglia risk gene linked to multiple sclerosis (MS), but its specific role in MS pathogenesis remains unclear. Through the use of Irf5^-/- mice, our study uncovers a non-canonical function of IRF5 in MS recovery. Irf5^-/- mice exhibited increased damage in an experimental autoimmune encephalomyelitis (EAE) model and demonstrated impaired oligodendrocyte recruitment into the lesion core following lysolecithin-induced demyelination. Transcriptomic and lipidomic analyses revealed that IRF5 has a role in microglia-mediated myelin phagocytosis, lipid metabolism, and cholesterol homeostasis. Indeed, Irf5^-/- microglia phagocytose myelin, but myelin debris is not adequately degraded, leading to an accumulation of lipid droplets, cholesterol esters, and cholesterol crystals within demyelinating lesions. This abnormal buildup can hinder remyelination processes. Importantly, treatments that promote cholesterol transport were found to reduce lipid droplet accumulation and mitigate the exacerbated damage in Irf5^-/- mice with EAE. Altogether, our study identified the antiviral transcription factor IRF5 as a key transcriptional regulator of lipid degradation and cholesterol homeostasis and suggest that loss of IRF5 function leads to pathogenic lipid accumulation in microglia, thereby obstructing remyelination. These data and the fact that Irf5 polymorphisms are significantly associated with MS, highlight IRF5 as a potential therapeutic target to promote regenerative responses.