Control of systemic and hepatic inflammation, in particular originating from monocytes/macrophages, is crucial to prevent liver fibrosis and its progression to end-stage cirrhosis. LC3-associated phagocytosis (LAP) is a non-canonical form of autophagy that shifts the monocyte/macrophage phenotype to an anti-inflammatory phenotype. In a recent study, we uncovered LAP as a protective mechanism against inflammation-driven liver fibrosis and systemic inflammation in the context of cirrhosis. We observed that LAP is enhanced in blood and liver monocytes from patients with liver fibrosis or those who progress to cirrhosis. Combining studies in which LAP was pharmacologically or genetically inactivated, we found that LAP limits inflammation in monocytes from cirrhotic patients, and the hepatic inflammatory profile in mice with chronic liver injury, resulting in anti-fibrogenic effects. Mechanistically, LAP-induced anti-inflammatory and antifibrogenic signaling results from enhanced expression of the Fc immunoreceptor FCGR2A/FcγRIIA and activation of an FCGR2A-mediated PTPN6/SHP-1 anti-inflammatory pathway, leading to increased engulfment of IgG into LC3 ⁺ phagosomes. In patients with cirrhosis progressing to multi-organ failure (acute-on chronic liver failure), LAP is lost in monocytes, and can be restored by targeting FCGR2A-mediated PTPN6/SHP-1 signaling. These data suggest that sustaining LAP may open novel therapeutic perspectives for patients with end-stage liver disease.

控制全身和肝脏的炎症，特别是源于单核细胞/巨噬细胞的炎症，对于预防肝纤维化及其发展为晚期肝硬化至关重要。LC3相关吞噬作用（LAP）是自噬的一种非规范形式，可将单核细胞/巨噬细胞表型转变为抗炎表型。在最近的一项研究中，我们发现LAP是针对肝硬化情况下炎症驱动的肝纤维化和全身性炎症的保护机制。我们观察到肝纤维化患者或肝硬化患者的血液和肝单核细胞中LAP增强。结合将LAP进行药理或遗传灭活的研究，我们发现LAP可以限制肝硬化患者单核细胞的炎症，并限制患有慢性肝损伤的小鼠的肝脏炎症状况，导致抗纤维化作用。从机制上讲，LAP诱导的抗炎和抗纤维化信号传导是由于Fc免疫受体FCGR2A /FcγRIIA的表达增强和FCGR2A介导的PTPN6 / SHP-1抗炎途径的激活，导致IgG吞入LC3的增加⁺吞噬体。在肝硬化进展为多器官功能衰竭（急性慢性肝功能衰竭）的患者中，LAP在单核细胞中丢失，可以通过靶向FCGR2A介导的PTPN6 / SHP-1信号传导来恢复。这些数据表明，维持LAP可能为晚期肝病患者打开新的治疗前景。