Description: The non-neural cholinergic system plays a fundamental role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase (ChAT), the enzyme catalyzing acetylcholine (ACh) biosynthesis, has been well documented in lymphocytes, its role in the myeloid compartment is less understood. Here, we identify a novel subset of ChAT-expressing cholinergic macrophages in the resolution phase of acute peritonitis. Using Chat-GFP reporter mice, we observed a marked upregulation of ChAT in monocyte-derived small peritoneal macrophages (SPMs) in response to Pam3CSK4 (Pam3), a Toll-like receptor (TLR) 1/2 agonist. These SPMs, phenotypically and transcriptionally distinct from tissue-resident large peritoneal macrophages (LPMs), upregulated ChAT expression mediated 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, indicating a unique triggering mechanism for ChAT expression in macrophages. Functionally, Chat deficiency in macrophages resulted in reduced efferocytosis of apoptotic neutrophils and a delayed resolution of peritonitis. This could be reversed by ACh supplementation, confirming the involvement of macrophage-derived cholinergic signals in regulating inflammation resolution. 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 macrophage-derived ACh in resolution of inflammation and highlight the importance of the non-neuronal cholinergic system in immune regulation.

Data type: Raw sequence reads

Sample scope: Multiisolate

Release date: 2024-05-04

Last updated: 2024-05-04

Data size: 318.57GB