CD36-mediated uptake of oxidized LDL induces double-negative regulatory T cell ferroptosis in metabolic dysfunction-associated steatotic liver disease

Yunxiong Wei; Yuan Jiang; Jingjing Zhu; Zihan Zhang; Mengyi Li; Shimeng Zheng; Xiyu Wang; Jie Sun; Changying Li; Wen Shi; Songlin Wang; Xinjuan Liu; Minjie Lin; Zhongtao Zhang; Dong Zhang; Guangyong Sun

doi:10.1016/j.metabol.2024.156127

CD36-mediated uptake of oxidized LDL induces double-negative regulatory T cell ferroptosis in metabolic dysfunction-associated steatotic liver disease

Metabolism. 2024 Dec 30:164:156127. doi: 10.1016/j.metabol.2024.156127. Online ahead of print.

Authors

Yunxiong Wei¹, Yuan Jiang², Jingjing Zhu², Zihan Zhang³, Mengyi Li⁴, Shimeng Zheng², Xiyu Wang², Jie Sun³, Changying Li⁵, Wen Shi³, Songlin Wang⁶, Xinjuan Liu⁷, Minjie Lin⁸, Zhongtao Zhang⁹, Dong Zhang¹⁰, Guangyong Sun¹¹

Affiliations

¹ Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
² Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
³ Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
⁴ General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
⁵ Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
⁶ Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China.
⁷ Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
⁸ Academic Affairs Department, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
⁹ General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. Electronic address: [email protected].
¹⁰ Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China. Electronic address: [email protected].
¹¹ Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. Electronic address: [email protected].

PMID: 39743040
DOI: 10.1016/j.metabol.2024.156127

Abstract

Background: Metabolic alterations have been shown to instigate liver inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanism is not fully elucidated. During MASLD progression, intrahepatic CD3⁺TCRαβ⁺CD4^-CD8^- double negative T regulatory cells (DNT) decrease cell survival and immunosuppressive function, leading to aggravated liver inflammation. In this study, we aim to reveal the underlying mechanisms that cause changes in DNT during MASLD progression.

Methods: The correlation of serum oxidized low-density lipoprotein (oxLDL) levels and DNT from patients with MASLD and MASLD mouse models were evaluated. The mechanisms of oxLDL affecting DNT survival and function were explored through transcriptome sequencing analysis, flow cytometry, and CUT & TAG experiments.

Results: Serum oxLDL levels are negative correlated with survival and functional molecule expression of circulating DNT in patients with MASLD and intrahepatic DNT in MASLD mouse models. Mechanistically, oxLDL increases DNT CD36 expression through the NF-κB pathway, leading to enhanced uptake of oxLDL and subsequent occurrence of ferroptosis and functional impairment. oxLDL enhances ferroptosis in DNT by upregulating acyl-CoA synthetase long chain family member 4 expression. By transferring CD36^-/- DNT into MASLD mice, we observe a significant reduction in ferroptosis and improved immune regulation in CD36^-/- DNT compared to wild type DNT. This improvement in DNT results in a notable enhancement of therapeutic efficacy against MASLD.

Conclusion: oxLDL induces a decline in the survival and immune regulatory function of DNT, subsequently weakening their role in maintaining liver immune homeostasis in MASLD. Specific targeting of CD36 to prevent ferroptosis in DNT may provide a novel therapeutic approach for the treatment of MASLD.

Keywords: ACSL4; CD36; Double negative T cells; Ferroptosis; Metabolic dysfunction-associated steatotic liver disease.