Rebalancing liver-infiltrating CCR3 + and CD206 + monocytes improves diet-induced NAFLD.

Melatonin has been reported to improve nonalcoholic fatty liver disease (NAFLD), and exploring the underlying mechanisms will be beneficial for better treatment of NAFLD. Choline-deficient high-fat diet (CDHFD)- and methionine/choline-deficient diet (MCD)-fed mice with melatonin intervention exhibit significantly decreased liver steatosis, lobular inflammation, and focal liver necrosis. Single-cell RNA sequencing reveals that melatonin selectively inhibits pro-inflammatory CCR3 monocyte-derived macrophages (MoMFs) and upregulates anti-inflammatory CD206 MoMFs in NAFLD mice. Liver-infiltrating CCR3CD14 MoMFs are also significantly increased in patients with NAFLD. Mechanistically, melatonin receptor-independent BTG2-ATF4 signaling plays a role in the regulation of CCR3 MoMF endoplasmic reticulum stress, survival, and inflammation. In contrast, melatonin upregulates CD206 MoMF survival and polarization via MT1/2 receptors. Melatonin stimulation also regulates human CCR3 MoMF and CD206 MoMF survival and inflammation in vitro. Furthermore, CCR3 depletion antibody monotherapy inhibits liver inflammation and improves NAFLD in mice. Thus, therapies targeting CCR3 MoMFs may have potential benefits in NAFLD treatment.