Immune-related GTPase M (IRGM1) regulates neuronal autophagy in a mouse model of stroke

Abstract

Autophagy is an important cellular recycling mechanism through self-digestion in responses to cellular stress such as starvation. Studies have shown that autophagy is involved in maintaining the homeostasis of the neural system during stroke. However, molecular mechanisms underlying neuronal autophagy in ischemic stroke remain poorly understood. Previously, we and others have shown that immune-related GTPase M (IRGM; termed IRGM1 in the mouse nomenclature) can regulate the survival of immune cells through autophagy in response to infections and autoimmune conditions. Here, using a permanent middle cerebral artery occlusion (pMCAO) mouse model, we found that IRGM1 was upregulated in the ischemic side of the brain, which was accompanied by a significant autophagic response. In contrast, neuronal autophagy was almost complete lost in Irgm1 knockout (KO) mice after pMCAO induction. In addition, the infarct volume in the Irgm1-KO pMCAO mice was significantly increased as compared to wild-type mice. Histological studies suggested that, at the early stage (within 24 h) of ischemia, the IRGM1-dependent autophagic response is associated with a protection of neurons from necrosis in the ischemic core but a promotion of neuronal apoptosis in the penumbra area. These data demonstrate a novel role of IRGM1 in regulating neuronal autophagy and survival during ischemic stroke.

Radiation persistently promoted oxidative stress, activated mTOR via PI3K/Akt, and downregulated autophagy pathway in mouse intestine

“…Indeed, accumulation of p62, which is an adaptor protein facilitating recruitment of ubiquitinated proteins to autophagosome via its interaction with LC3 and Gabarap family of proteins and is degraded during autophagic process [43], further argues in favor of autophagy downregulation after radiation exposure. Considering that Eif2ak3 and Irgm1 respectively are required for endoplasmic reticulum (ER) [44], and bacterial pathogen [45] mediated stress-induced autophagy activation, decreased expression of these factors will cause a faulty autophagic response to ER stress and immune challenges and increased vulnerability of intestinal cells to functional deregulation and pathologic infection. On the contrary, increased level of Snca [46] as well as ligand-mediated activation of Fas [47] is known to activate autophagy and downregulation of both the factors observed in our study further supports long-term downregulatory effects of sub-lethal radiation exposure on autophagy.…”

Autophagy Mediates Astrocyte Death During Zinc-Potentiated Ischemia–Reperfusion Injury

“…However, others have shown that autophagy can be neuroprotective by removing dysfunctional mitochondria [39]. Autophagic neuroprotection may also involve immune responses and other neuroprotective pathways [40]. Overall, the effect of autophagy in cerebral ischemia is likely complex with the extent and context of autophagy being key factor.…”

Altering Autophagy: Mouse Models of Human Disease

“…However in parallel with in vitro data, IRGM1 has recently been shown to induce autophagy in a mouse model of stroke. The promotion of autophagy, most likely at the level of LC3I to LC3II conversion, was generally protective [51].…”