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

ABSTRACT: Melatonin has been reported to improve NAFLD, exploring the underlying mechanisms will be beneficial for better treatment of NAFLD. CDHFD- and MCD-fed mice with melatonin intervention exhibited significantly decreased liver steatosis, lobular inflammation, and focal liver necrosis. Single-cell RNA sequencing revealed melatonin selectively inhibited proinflammatory CCR3+ MoMFs, and upregulated anti-inflammatory CD206+ MoMFs in NAFLD mice. Hepatic infiltrated CCR3+CD14+ MoMFs is also significantly increased in patients with NAFLD. Mechanistically, melatonin receptor independent BTG2-ATF4 signaling plays a vital role in the regulation of CCR3+ MoMFs endoplasmic reticulum stress, survival, and proinflammation by melatonin. In contrast, melatonin upregulated CD206+ MoMFs survival and polarization via MT1/2 receptors. Melatonin stimulation also regulates human CCR3+ MoMFs and CD206+ MoMFs survival and inflammation in vitro. Furthermore, CCR3 depletion antibody monotherapy decreased liver inflammation and improved NAFLD in mice. Thus, Therapies targeting CCR3+ MoMFs may have potential benefits in NAFLD treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE204821 | GEO | 2023/06/04

REPOSITORIES: GEO

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

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