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

Guangyong Sun; Yaning Wang; Lu Yang; Zihan Zhang; Yushang Zhao; Zongshan Shen; Xiaotong Han; Xiaonan Du; Hua Jin; Changying Li; Songlin Wang; Zhongtao Zhang; Dong Zhang

doi:10.1016/j.celrep.2023.112753

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

Cell Rep. 2023 Jul 25;42(7):112753. doi: 10.1016/j.celrep.2023.112753. Epub 2023 Jul 7.

Authors

Guangyong Sun¹, Yaning Wang², Lu Yang³, Zihan Zhang⁴, Yushang Zhao⁴, Zongshan Shen⁵, Xiaotong Han⁴, Xiaonan Du⁴, Hua Jin⁴, Changying Li⁴, Songlin Wang⁵, Zhongtao Zhang⁶, Dong Zhang⁷

Affiliations

¹ General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China.
² Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China.
³ General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
⁴ Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China.
⁵ Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China.
⁶ General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China.
⁷ General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China. Electronic address: zhangd@ccmu.edu.cn.

PMID: 37421620
DOI: 10.1016/j.celrep.2023.112753

Abstract

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 CCR3⁺CD14⁺ 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.

Keywords: BTG2; CCR3; CD206; CP: Immunology; NAFLD; melatonin; monocytes-derived macrophages.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Choline
Diet, High-Fat / adverse effects
Humans
Immediate-Early Proteins*
Inflammation
Liver
Melatonin*
Methionine
Mice
Mice, Inbred C57BL
Monocytes
Non-alcoholic Fatty Liver Disease* / drug therapy
Receptors, CCR3
Tumor Suppressor Proteins

Substances

Choline
Immediate-Early Proteins
Melatonin
Methionine
Receptors, CCR3
Tumor Suppressor Proteins