NLRP6 is essential for TREM2-alleviated cardiac ischemia/reperfusion injury via affecting PANoptosis

Ischemia/reperfusion (I/R) injury is characterized by the activation of multiple regulated cell death pathways, including pyroptosis, apoptosis, and necroptosis-collectively known as PANoptosis. Nevertheless, the molecular determinants driving myocardial PANoptosis remain poorly defined. Triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune modulator, has been implicated in diverse pathological contexts, but its role in cardiac I/R injury is unclear. In parallel, NOD-like receptor family pyrin domain-containing 6 (NLRP6) has recently been recognized as a regulator of inflammatory and cell death pathways, yet its contribution to cardiovascular pathology remains largely unknown. Here, we investigated whether TREM2 mitigates NLRP6-related PANoptosis following heart I/R and explored the underlying mechanisms. TREM2-knockout (KO), NLRP6 KO, and wild-type (WT) mice with solube TREM2 (sTREM2) administered exclusively to WT mice were subjected to left anterior descending coronary artery ligation. TREM2 was induced in cardiac tissue and cardiomyocytes after I/R or hypoxia/reoxygenation (HR). Loss of TREM2 exacerbated necroptosis and acute myocardial injury, whereas sTREM2 administration markedly attenuated these effects in vivo. NLRP6 protein expression gradually increased after reperfusion, peaking at 48 h during I/R injury. Mechanistically, both in vivo and in vitro evidence indicated that TREM2 regulates NLRP6 and high-mobility group box 1 (HMGB1) expression by inhibiting toll like receptor4 (TLR4)/nuclear factor-κB (NF-κB) activation, thereby restraining PANoptosis in cardiomyocytes. Importantly, inhibiting NLRP6 or HMGB1 largely reversed the pro-death effects induced by TREM2 deficiency. Clinically, plasma concentrations of NLRP6, TREM2, and HMGB1 were markedly elevated in patients with acute myocardial infarction (AMI). Together, these findings identify TREM2 as a critical negative regulator of myocardial PANoptosis through modulation of the HMGB1/TLR4/NF-κB/NLRP6 axis. Targeting the TREM2-NLRP6 signaling pathway may offer a promising therapeutic approach against cardiac I/R injury.