NLRP3/Caspase-1 Regulate Macrophage Efferocytosis by Modulating ADAM17-Mediated MerTK Cleavage in Liver Ischemia–Reperfusion Injury

In liver ischemia-reperfusion injury (LIRI), macrophage clearance of apoptotic cells via efferocytosis is crucial to prevent excessive inflammation and tissue damage. Here, we investigate the role of nucleotide-binding oligomerization domain-like receptor protein 3/cysteine-aspartate protease-1 (NLRP3/Caspase-1) signaling in modulating macrophage efferocytosis during LIRI. We observed robust activation of the NLRP3/Caspase-1 pathway during the early phase of LIRI. Genetic ablation of <i>Nlrp3</i> or <i>Caspase-1</i> substantially reduced LIRI severity. Notably, myeloid-specific <i>Nlrp3</i> knockout mice exhibited less severe LIRI compared to hepatocyte-specific <i>Nlrp3</i> knockouts, whereas macrophage-specific overexpression of <i>Caspase-1</i> exacerbated tissue injury. Mechanistically, NLRP3/Caspase-1 activation enhances a disintegrin and metalloprotease protein-17 (ADAM17)-mediated cleavage of Mer proto-oncogene tyrosine kinase (MerTK), leading to impaired efferocytosis. Pharmacological inhibition of ADAM17 restored macrophage efferocytic capacity and alleviated LIRI. Clinically, elevated serum levels of soluble MerTK (s-Mer) correlated with hepatic injury severity and Caspase-1 activation in patients after partial hepatectomy or liver transplantation. Our findings suggest a potential therapeutic strategy for LIRI prevention and treatment.