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There are several possible mechanisms about ischemia\/reperfusion injury, but the influence on intestinal myenteric neurons and the underlying mechanism are still unclear. C57BL6\/J mice were used to establish the ischemia\/reperfusion model <jats:italic>in vivo<\/jats:italic>. Peritoneal macrophages were used for ATP depletion and hypoxia\/reoxygenation experiment <jats:italic>in vitro<\/jats:italic>. L-cysteine, as the substrate of hydrogen sulfide, is involved in many physiological and pathological processes, including inflammation, metabolism, neuroprotection, and vasodilation. In the current study, we confirmed that intestinal ischemia\/reperfusion led to the injury of myenteric neurons. From experiments <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>, we demonstrated that L-cysteine protected myenteric neurons from the injury. AOAA reversed the protective effect of L-cysteine. Also, L-cysteine played a protective role mainly by acting on intestinal macrophages via decreasing the expression of NLRP3, cleaved caspase-1, and mature IL-1\u03b2. L-cysteine increased cystathionine beta synthase and H<jats:sub>2<\/jats:sub>S produced by intestinal macrophages to protect myenteric mature neurons and enteric neural precursor cells from apoptosis. Moreover, the addition of IL-1\u03b2-neutralizing antibody alleviated the injury of myenteric neurons and enteric neural precursor cells caused by intestinal ischemia\/reperfusion. Our study provided a new target for the protection of myenteric neurons in clinical intestinal ischemia\/reperfusion injury.<\/jats:p>","DOI":"10.3389\/fphar.2022.899169","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T06:10:57Z","timestamp":1654668657000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["L-Cysteine Alleviates Myenteric Neuron Injury Induced by Intestinal Ischemia\/Reperfusion via Inhibitin the Macrophage NLRP3-IL-1\u03b2 Pathway"],"prefix":"10.3389","volume":"13","author":[{"given":"Yifei","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanyong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1038\/nri1664","article-title":"Interleukin-1 and Neuronal Injury","volume":"5","author":"Allan","year":"2005","journal-title":"Nat. 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