Defective cholesterol clearance limits remyelination in the aged central nervous system

Abstract

Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation and phagolysosomal membrane rupture and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters, including apolipoprotein E. Stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals and thereby inducing a maladaptive immune response that impedes tissue regeneration.

P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis

“…The role of inflammation in promoting neural repair is gaining increasing recognition. Products of macrophages as well as of microglia, their CNS counterparts, facilitate the regeneration of axons (David et al, 1990;Yin et al, 2006) and promote remyelination in animal models of demyelination as their deficiency retards the process of remyelination (Kotter et al, 2005;Kondo et al, 2011;Miron et al, 2013;Sun et al, 2017;Cantuti-Castelvetri et al, 2018). However, the innate immune system capacity to restore myelination in the context of MS depends on microglia/macrophage polarization state.…”

“…The benefits of microglia/macrophage may be attributed to being required in clearing myelin debris after a demyelinating episode (Kotter et al, 2006;Neumann et al, 2009;Lampron et al, 2015;Cantuti-Castelvetri et al, 2018), as well as their release of a variety of growth factors into the injured CNS that favor oligodendrocyte differentiation (Miron et al, 2013). Phagocytosis of myelin is more robust in anti-inflammatory microglia than in pro-inflammatory microglia (Durafourt et al, 2012;Healy et al, 2016).…”

“…Thus, phagocytosis of myelin controls microglia/macrophage inflammatory response (Kroner et al, 2014). Recently, it has been described that phagocytosis of myelin in aged microglia/macrophages after demyelination results in cholesterol accumulation in these cells, leading to a maladaptive inflammatory response with inflammasome activation that impairs remyelination (Cantuti-Castelvetri et al, 2018).…”

Inhibitory milieu at the multiple sclerosis lesion site and the challenges for remyelination

“…The phagocytic activities of macrophages and microglia are essential for the removal of inhibitory myelin debris (Ousman & David, ), and deficits in myelin phagocytosis prevent remyelination in vivo (Lampron et al, ). Furthermore, factors such as aging impair phagocytic activity and may contribute to remyelination failure in MS (Cantuti‐Castelvetri et al, ; Natrajan, Komori, et al, ; Ruckh et al, ). Additionally, astrocytes contribute to the clearance of myelin debris through both myelin phagocytosis (Liddelow et al, ) and the recruitment of macrophages and microglia to sites of demyelination (Ponath et al, ; Skripuletz et al, ).…”

“…Cantuti-Castelvetri et al, 2018;Natrajan, Komori, et al, 2015;Ruckh et al, 2012). Additionally, astrocytes contribute to the clearance of myelin debris through both myelin phagocytosis(Liddelow et al, 2017) and the recruitment of macrophages and microglia to sites of demyelination(Ponath et al, 2017;Skripuletz et al, 2013).…”