BET proteins inhibitor JQ1 impairs GM-CSF-promoted peritoneal macrophage self-renewal and IL-4-induced alternative polarization

Xue Chen; Qiong Jiang; Laibin Ren; Hongyu Ren; Haizhao Xu; Jinyong Wang; Pengbo Wang; Shanze Chen; Yuanqi Hua; Sichong Ren; Ning Huang; Lanlan Zhang; Lijia Xiao

doi:10.1016/j.intimp.2023.110942

BET proteins inhibitor JQ1 impairs GM-CSF-promoted peritoneal macrophage self-renewal and IL-4-induced alternative polarization

Int Immunopharmacol. 2023 Nov;124(Pt A):110942. doi: 10.1016/j.intimp.2023.110942. Epub 2023 Sep 15.

Authors

Xue Chen¹, Qiong Jiang², Laibin Ren³, Hongyu Ren³, Haizhao Xu⁴, Jinyong Wang², Pengbo Wang⁵, Shanze Chen⁶, Yuanqi Hua³, Sichong Ren⁷, Ning Huang⁸, Lanlan Zhang⁹, Lijia Xiao¹⁰

Affiliations

¹ Department of Clinical Laboratory Medicine Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong, China.
² Shenzhen Institute of Respiratory Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518107, Guangdong, China.
³ Department of Pathophysiology, West China College of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China.
⁴ Department of Respiratory, The First Affiliated Hospital, School of Medicine, Southern University of Science and Technology, 518055, Guangdong, China.
⁵ School of Professional Studies, Columbia University, NY 10027, NY, USA.
⁶ Shenzhen Institute of Respiratory Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518107, Guangdong, China; Department of Pathophysiology, West China College of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China.
⁷ Department of Nephrology, the First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan, China.
⁸ Department of Pathophysiology, West China College of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: Huangning515@163.com.
⁹ Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: llzhang@scu.edu.cn.
¹⁰ Department of Clinical Laboratory Medicine Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong, China. Electronic address: x190791844@126.com.

PMID: 37716160
DOI: 10.1016/j.intimp.2023.110942

Abstract

Peritoneal macrophages (PMs), which resided in peritoneal cavity, are crucial to maintain tissue homeostasis and immunity. Macrophage self-renewal and polarization states are critical for PM population homeostasis and function. However, the underlying molecular mechanism that regulates self-renewal and polarization of PMs is still unclear and needs to be explored. Here, we demonstrated that PMs self-renewal was stimulated by granulocyte macrophage colony-stimulating factor (GM-CSF), but not by macrophage colony-stimulating factor (M-CSF). Pharmacological inhibition of Bromodomain & Extraterminal (BET) Proteins by either JQ1 or ARV-825 significantly reduced GM-CSF-dependent peritoneal macrophage self-renewal by abrogating cell proliferation and decreasing self-renewal-related gene expression, such as MYC and Klf4, at transcriptional and protein levels. In addition, transcriptomic analysis showed that JQ1 blocked alternative PMs polarization by downregulating key transcriptional factor IRF4 expression, but not the activation of AKT or STAT6 in PMs. These findings illustrated that the significance of BET family proteins in GM-CSF-induced PMs self-renewal and IL-4-induced alternative polarization.

Keywords: Alternative PMs polarization; BET Proteins; JQ1; Peritoneal macrophages; Self-renewal.