Cholinergic macrophages promote the resolution of peritoneal inflammation

• 成果类型: Article
• 署名作者: Luo, Shufeng; Lin, Huiling; Wu, Chong; Zhu, Lan; Hua, Qiaomin; Wang, Lu; Fan, Xiaoli; Zhao, Kai-Bo; Liu, Gaoteng; Wang, Yuting; Chen, Hai-Tian; Xu, Li; Zheng, Limin
• 署名单位: Sun Yat Sen University; State Key Lab Oncology South China; Sun Yat Sen University; Sun Yat Sen University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9097
• DOI: 10.1073/pnas.2402143121
• 发表日期: 2024-07-02
• 关键词: t-cells; SYSTEM; acetylcholine; polarization; mediators; signals

摘要

The non- neural cholinergic system plays a critical role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase (ChAT), the enzyme catalyzing acetylcholine biosynthesis, has been well documented in lymphocytes, its role in the myeloid compartment is less understood. Here, we identify a significant population of macrophages (M(I)s) expressing ChAT and synthesizing acetylcholine in the resolution phase of acute peritonitis. Using Chat- GFP reporter mice, we observed marked upregulation of ChAT in monocyte- derived small peritoneal M(I)s (SmPMs) in response to Toll- like receptor agonists and bacterial infections. These SmPMs, phenotypically and transcriptionally distinct from tissue- resident large peritoneal macrophages, up- regulated ChAT expression through a MyD88- dependent pathway involving MAPK signaling. Notably, this process was attenuated by the TRIF- dependent TLR signaling pathway, and our tests with a range of neurotransmitters and cytokines failed to induce a similar response. Functionally, Chat deficiency in M(I)s led to significantly decreased peritoneal acetylcholine levels, reduced efferocytosis of apoptotic neutrophils, and a delayed resolution of peritonitis, which were reversible with exogenous ACh supplementation. Intriguingly, despite B lymphocytes being a notable ChAT- expressing population within the peritoneal cavity, Chat deletion in B cells did not significantly alter the resolution process. Collectively, these findings underscore the crucial role of M(I)- derived acetylcholine in the resolution of inflammation and highlight the importance of the non- neuronal cholinergic system in immune regulation.