Multiple sclerosis (MS) is a devastating neurological disease and one of the most prevalent autoimmune disorders in the Western world. Foamy macrophages loaded with myelin-derived lipid droplets (LDs) are a pathological hallmark of MS lesions.
Recent research showed that excessive accumulation of intracellular LDs induces a pro-inflammatory macrophage phenotype, which promotes neuroinflammation and impairs central nervous system (CNS) repair. To date, however, the molecular pathways responsible for excessive accumulation of LDs in lesion-associated macrophages remain to be uncovered.
Our findings indicate that perturbed activity of multiple metabolic pathways underpins excessive intracellular LD accumulation in foamy macrophages, thereby driving the induction of a disease-promoting macrophage phenotype in MS lesions. First, we find that sustained intracellular accumulation of myelin is associated with impaired lipophagy, a selective form of autophagy involved in LD turnover. Second, we demonstrate that increased abundance of the LD protein perilipin-2 (PLIN2) impairs lipolysis-mediated degradation of LDs. Finally, our results indicate that excessive myelin uptake by macrophages hampers cholesterol efflux by promoting the ubiquitination and degradation of the cholesterol efflux transporter ABCA1 via the ubiquitin E3 ligase A (UBE3A). Importantly, pharmacological activation of lipophagy and genetic loss of PLIN2 and UBE3A reduced cellular LD load in foamy macrophages, induced an anti-inflammatory phenotype of these cells, and enhanced CNS repair in ex vivo and in vivo toxin-induced demyelination models. In aggregate, obtained results provide increased insight into MS lesion pathology, and identify multiple novel pathways as promising therapeutic targets to boost CNS repair in MS and other neurological diseases characterized by the presence of foamy macrophages.