TREML2 Modulates Microglial Phagocytosis of Myelin Debris via TLR9 in Chronic Cerebral Ischemia

Demyelination is a significant pathological feature of chronic cerebral ischemia. Recent evidence suggested that microglia played a protective role in mitigating brain ischemic injury via phagocytosis of myelin debris resulting from demyelination. Triggering receptor expressed on myeloid cells-like 2 (TREML2) is a newly discovered inflammation-associated transmembrane receptor expressed by microglia. To date, whether microglial TREML2 contributes to the phagocytosis of myelin debris in chronic cerebral ischemia has not been fully clarified. In this study, employing a bilateral carotid artery stenosis animal model and a CoCl 2 -treated cellular model, we demonstrated for the first time that microglial TREML2 expression was upregulated in response to chronic cerebral ischemia. Utilizing Treml2 -knockout mice, we provided the first evidence that Treml2 deficiency alleviated demyelination and cognitive deficits induced by chronic cerebral ischemia. Furthermore, this protective effect might be attributed to the microglial M2-type polarization and enhanced phagocytosis of myelin debris, both of which were induced by the Treml2 deficiency. Additionally, we showed that TREML2 regulated microglial phagocytosis of myelin debris via toll-like receptor 9 under ischemic conditions. These findings elucidated the mechanisms by which microglia modulated the phagocytosis of myelin debris in response to brain ischemic injury and suggested that inhibition of TREML2 might represent a novel therapeutic strategy for treating demyelination and cognitive decline induced by chronic cerebral ischemia.