TRPM2 overactivation drives hyperlipidemia-induced dysfunction of myeloid cells and neurovascular units

Hyperlipidemia induces cellular dysfunction and is strongly linked to various diseases. The transient receptor potential channel melastatin 2 (TRPM2) plays a critical role in endothelial injury, immune cell activation, and neuronal death. We reveal that TRPM2 expression in human peripheral leukocytes strongly correlates with plasma lipid levels. In middle-aged Apoe^-/- mice, global, myeloid, and endothelial TRPM2 knockout or TRPM2 inhibition abolishes the hyperlipidemia-induced exacerbation of ischemic brain injury suggesting that TRPM2 overactivity caused by hyperlipidemia predisposes these cells to dysfunction during ischemia. Using a clinically relevant ischemic brain injury mouse model, we demonstrate TRPM2's pivotal role in mediating hyperlipidemia's detrimental effects on myeloid cells and neurovascular units. Our findings suggest that TRPM2 is a promising therapeutic target for alleviating neurodegenerative diseases exacerbated by hyperlipidemia, such as ischemic stroke. These results also highlight TRPM2 expression in peripheral blood as a potential biomarker for predicting stroke outcomes in hyperlipidemic patients.