Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination

Abstract

The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.

Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey

“…The correlation of increased phagocytic phenotype (amoeboid cells) with increased cognitive decline reported here and the age-related increase in myelin damage reported in this same model (see Peters and Kemper 2012 for review) likely means that phagocytosis is not sufficient to effectively remove damaged myelin (Ruckh et al 2012;Natrajan et al 2015). Hence, the observed increase in Gal-3-positive microglia with age could indicate that microglia have been Bprimed^for phagocytosis by detection of deteriorating myelin, but are either dysfunctional or the amount/rate of myelin damage is too much for microglia to efficiently phagocytose the debris.…”

“…This is in contrast to in vitro studies that report macrophages, such as microglia, phagocytose myelin at a greater rate than astrocytes (Williams et al 1994). Other studies report that myelin phagocytosis is impaired with age (Ruckh et al 2012;Natrajan et al 2015) and can be inhibited by proinflammatory cytokines (Brück et al 1992;Liu et al 2006). Thus, it is possible that the chronically proinflammatory microglia of the aging brain could slow the removal and phagocytosis of myelin debris (Rawji et al 2016).…”

“…Hence, the observed increase in Gal-3-positive microglia with age could indicate that microglia have been Bprimed^for phagocytosis by detection of deteriorating myelin, but are either dysfunctional or the amount/rate of myelin damage is too much for microglia to efficiently phagocytose the debris. As more myelin debris accumulates and is not repaired, a vicious cycle could result in which more microglia are recruited and release pro-inflammatory cytokines, but fail to remove sufficient myelin debris to allow for remyelination and resolution of inflammation (Ruckh et al 2012;Natrajan et al 2015).…”

“…Studies on peripheral immunity have shown a loss of phagocytic capacity and function in macrophages with age (Plowden et al 2004), although this result is not consistent across all studies (Gardner et al 1981) and may differ between inflammatory cell types (Linehan et al 2014). Cultured macrophages from aged humans have a diminished phagocytic capacity for myelin debris (Natrajan et al 2015), and in vivo studies have shown that the rate of remyelination is reduced in aged rodents but can be restored with an infusion of monocytes from young animals (Ruckh et al 2012). Finally, phagocytic activation of microglia and size of microglial lysosomes increases with age in addition to an increase in microglia adjacent to and contacting myelin (Safaiyan et al 2016).…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…Comparing mononuclear phagocytes between young and old mice, aged macrophages, and microglia exhibited reduced motility in response to laser-induced injury and extracellular ATP [197]. In demyelinating models, reduced migration of mononuclear cells [198], and impaired clearance of myelin debris in macrophages accompanied by an age-associated delay in remyelination have been observed [199][200][201]. Additionally, microglia isolated from aged mice displayed a reduced capability to engulf Aβ compared with young mice [202,203].…”