Rewiring of fatty acid synthesis in phagocytes and oligodendrocytes regulates central nervous system remyelination

Abstract

Phagocytes like macrophages and microglia play a dual role in lesion progression in multiple sclerosis (MS) by promoting both inflammation and remyelination in the central nervous system (CNS). Excessive uptake of myelin by macrophages and microglia during demyelination results in enhanced inflammatory activation of these phagocytes and impairs oligodendrocyte-mediated remyelination. This functional alteration is accompanied by rewiring of fatty acid synthesis (FAS) in both phagocytes and oligodendrocytes, marking this pathway as a possible therapeutic target for decelerating MS lesion progression. Hence, by using in vitro, ex vivo and in vivo models we studied if inhibition of FAS altered inflammation, myelination, and oligodendrocyte precursor cell (OPC) differentiation. We found that inhibiting these myelin-induced changes in FAS halts foam cell formation by facilitating ABCA1-mediated cholesterol efflux in phagocytes, reducing inflammation, and enhancing the production of neurotrophic factors in vitro. Similarly, counteracting FAS in OPCs increases the differentiation towards myelin-producing oligodendrocytes and their migration capacity in vitro. Lipidomic analyses revealed metabolic alterations in lipid species underlying these altered phenotypes. These findings were confirmed in ex vivo and in vivo models for remyelination by generating cell-specific and FAS enzyme knockout mice. Phagocyte-specific FAS enzyme knockout effectively reduces lipid load and improves CNS repair. This effect is even larger in full FAS enzyme knockout, thereby providing evidence that FAS is a multifaceted target that enhances remyelination through the modulation of multiple cell types. Altogether, our results indicate that metabolic rewiring of FAS underlies the inflammatory phenotype of phagocytes and modulates the remyelinating capacity of oligodendrocytes. Hereby, FAS provides a novel therapeutic target for inducing CNS repair in MS.