Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development

Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggres-sive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persis-tent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutri-tion led to the production of proinflammatory cytokines TNF and IL-1b in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.

Automated summary

Obesity-induced chronic liver inflammation, a characteristic of NASH, is sustained in the liver through the macrophage phagocytic receptor TREM2. However, prolonged hypernutrition leads to the shedding of TREM2, resulting in the accumulation of dying hepatocytes and augmenting proinflammatory cytokine production. This vicious cycle drives the transition from simple steatosis to NASH, highlighting impaired macrophage efferocytosis as a key pathogenic event.