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 Nlrp3 or Caspase-1 substantially reduced LIRI severity. Notably, myeloid-specific Nlrp3 knockout mice exhibited less severe LIRI compared to hepatocyte-specific Nlrp3 knockouts, whereas macrophage-specific overexpression of Caspase-1 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.