Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system

Abstract

Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.

Microglia Diversity in Health and Multiple Sclerosis

“…In addition to this dysregulation in growth factor kinetics, lesions from ageing rodents displayed an accumulation of inhibitory myelin debris, suggesting that macrophages' and microglia's phagocytic capacity becomes impaired with ageing (148). Several studies have now highlighted a deficiency in the ability of ageing microglia and macrophages to phagocytose myelin debris (130,133,153). These alterations have been attributed to a disruption in retinoid X receptor signalling and a decrease in the expression of the scavenger receptor Cd36 (130,133).…”

“…Several studies have now highlighted a deficiency in the ability of ageing microglia and macrophages to phagocytose myelin debris (130,133,153). These alterations have been attributed to a disruption in retinoid X receptor signalling and a decrease in the expression of the scavenger receptor Cd36 (130,133). In addition to deficiencies in the initial engulfment of myelin debris, another group identified disruptions in the lysosomal processing and subsequent cholesterol efflux of ingested myelin (71,131).…”

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…Interestingly, aging is associated with remyelination failure and is accompanied by a decrease in the ability of microglial cells to phagocytose myelin. As was recently shown, the reduced expression of the scavenger receptor CD36 could be the reason for this reduced phagocytic activity [63]. In summary, astrocytes and microglia cells are important regulators of the pathology of MS diseases, and it is promising to shape their function through therapeutic intervention.…”

Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions

“…Its inhibition promotes the clearance of myelin debris in vivo and reprograms microglia towards a homeostatic transcriptional state leading to improvement of cognitive function in aged mice (Pluvinage et al, 2019). By up-regulating the expression of the scavenger receptor CD36, niacin (also called vitamin B3) induces myelin phagocytosis through binding its receptor, hydroxycarboxylic acid receptor 2, both in vitro and in vivo (Rawji et al, 2020).…”