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

Highlights•TRPM2 in peripheral leukocytes correlates with plasma lipid levels in humans•TRPM2 drives the abnormal activation of peripheral leukocytes induced by lipids•Hyperlipidemia upregulates TRPM2 expression, enhancing ischemic vulnerability•TRPM2 inhibition mitigates ischemic stroke aggravated by hyperlipidemiaSummaryHyperlipidemia 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.Graphical abstract