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

## TL;DR

This study shows that the NLRP3/Caspase-1 pathway worsens liver injury by impairing macrophage cleanup of dead cells, and blocking ADAM17 can help.

## Contribution

The study reveals a novel mechanism where NLRP3/Caspase-1 signaling impairs efferocytosis via ADAM17-mediated MerTK cleavage in liver injury.

## Key findings

- NLRP3/Caspase-1 activation during LIRI impairs macrophage efferocytosis through ADAM17-mediated MerTK cleavage.
- Genetic ablation of Nlrp3 or Caspase-1 reduces LIRI severity, especially in myeloid cells.
- Pharmacological ADAM17 inhibition restores efferocytosis and reduces liver injury in mice.

## Abstract

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.