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 (Mϕs) 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 Mϕs (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 Mϕs 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 Mϕ-derived acetylcholine in the resolution of inflammation and highlight the importance of the non-neuronal cholinergic system in immune regulation.

中文翻译：

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胆碱能巨噬细胞促进腹膜炎症的消退


非神经胆碱能系统在调节免疫平衡和组织稳态中发挥着关键作用。虽然胆碱乙酰转移酶（ChAT）（一种催化乙酰胆碱生物合成的酶）在淋巴细胞中的表达已得到充分记录，但其在骨髓室中的作用却知之甚少。在这里，我们确定了在急性腹膜炎消退阶段表达 ChAT 并合成乙酰胆碱的大量巨噬细胞 (Mφs)。使用 Chat -GFP 报告小鼠，我们观察到单核细胞来源的小腹膜 Mphis (SmPM) 中 ChAT 显着上调，以响应 Toll 样受体激动剂和细菌感染。这些 SmPM 在表型和转录上与组织驻留的大型腹膜巨噬细胞不同，它们通过涉及 MAPK 信号传导的 MyD88 依赖性途径上调 ChAT 表达。值得注意的是，这个过程被 TRIF 依赖性 TLR 信号通路减弱，并且我们对一系列神经递质和细胞因子的测试未能诱导类似的反应。从功能上讲，Mphis 中的 Chat 缺陷导致腹膜乙酰胆碱水平显着降低，凋亡中性粒细胞的胞吞作用减少，以及腹膜炎的延迟消退，这些通过补充外源性乙酰胆碱是可逆的。有趣的是，尽管 B 淋巴细胞是腹膜腔内值得注意的 ChAT 表达群体，但 B 细胞中的 Chat 缺失并没有显着改变解析过程。总的来说，这些发现强调了 Mφ 衍生的乙酰胆碱在炎症消退中的关键作用，并强调了非神经元胆碱能系统在免疫调节中的重要性。