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

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Acta Neuropathologica volume 139, pages893–909 (2020)Cite this article

Correction to this article was published on 24 March 2020

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.

Introduction

The loss of the myelin sheath has significant consequences for axonal health and conduction velocity [172942]. Although demyelinated axons have mechanisms to compensate for the loss of the insulative myelin sheath, these axons are ultimately more prone to degeneration. Remyelination is an endogenous process that restores rapid signal propagation and protects axons, but the process is usually incomplete and becomes inefficient with advanced age in rodents [47]. Both intrinsic changes in the oligodendrocyte progenitor cell (OPC) population as well as the extrinsic lesion microenvironment are thought to underlie the decreased remyelination efficiency in older animals after demyelination, likely accelerating their rate of axonal loss [51235414546].

Innate immune cells such as resident microglia and infiltrating macrophages are critical components to successful remyelination, as they release important growth factors and clear inhibitory myelin debris [523243041]. Several studies have associated the reduced remyelination of older animals with a dysregulated innate immune response that manifests as delayed recruitment of macrophages/microglia into lesions [53], and their deficient motility and phagocytosis of myelin debris within lesions [534394143]. Heterochronic parabiosis of older demyelinated mice paired with young mice resulted in infiltration of young macrophages and enhanced remyelination [41]. These results of parabiotic young macrophages altering the inhibitory lesion microenvironment of older mice suggest that pharmacological stimulation is a practical means to rejuvenate deficient macrophages/microglia to promote remyelination in older individuals.

We sought to identify a clinically approved medication to stimulate the beneficial properties of macrophages/microglia for remyelination in subjects with increasing age. By screening a library of 1040 mainly generic medications for the capacity to activate macrophages/microglia, we discovered niacin, or vitamin B3, to enhance macrophage/microglia cytokine secretion and phagocytosis in vitro. The screening results led us to investigate whether systemic niacin therapy in the lysolecithin model of demyelination could alter lesional macrophages/microglia to foster myelin repair in 9–12-month-old (henceforth referred to as middle-aged) mice. Our collective results highlight the deficits in debris removal in lesions of middle-aged compared to young 2–3-month-old animals, and they identify a novel, clinically tolerable medication that restores critical functions of macrophages/microglia to promote aging-deficient remyelination.

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