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A key DAMP, extracellular cold-inducible RNA-binding protein (eCIRP), exacerbates inflammation in reperfusion injury, contributing to organ failure and death. Apoptosis inhibitor of macrophage (AIM or CD5L) is a glycoprotein secreted by macrophages which can influence the activity of immune cells. We seek to investigate AIM expression in ischemia\/reperfusion (I\/R) and elucidate its anti-inflammatory role in macrophages and intestinal epithelial cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male mice underwent occlusion of the superior mesenteric artery for 60\u00a0min, followed by reperfusion for 4\u00a0h before sample collection. AIM expression in blood and tissue was evaluated by qPCR, Western blot, and ELISA. Primary peritoneal macrophages from male mice, IEC-6 intestinal epithelial cells, and RAW 264.7 macrophages were stimulated with recombinant mouse (rm) CIRP (denoted eCIRP) and treated with rmAIM. Cytokine levels were assessed by ELISA and qPCR. Metabolic function was measured in macrophages using the Agilent Seahorse XF Pro analyzer. Interactions involving AIM, eCIRP, and eCIRP\u2019s receptors, Toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells-1 (TREM-1), were elucidated by in silico approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Pulmonary AIM mRNA expression decreased by 55.9% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.018), and protein levels decreased by 26.9% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.032) in gut I\/R mice compared to sham mice. Plasma AIM concentration decreased by 22.0% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0362) in gut I\/R mice compared to sham. eCIRP treatment increased pro-inflammatory cytokine production by macrophages and intestinal epithelial cells. This increase was significantly attenuated by co-treatment with rmAIM. Macrophages also increased basal oxygen consumption rate by 66.7% and ATP production by 70.3% when treated with rmAIM compared to eCIRP stimulation alone (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). Computational modeling predicted strong interactions between AIM and eCIRP\u2019s receptors, TLR4 and TREM-1, and showed that the presence of AIM altered eCIRP\u2019s binding to these receptors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In male mice, gut I\/R decreases AIM protein levels and mRNA expression in the lungs as well as AIM plasma concentration. AIM reduces eCIRP-induced pro-inflammatory cytokine production in macrophages, potentially by inhibiting eCIRP\u2019s binding to TLR4 and TREM-1. These findings suggest AIM is a promising therapeutic candidate in males with gut I\/R.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-025-01385-1","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T13:11:14Z","timestamp":1761743474000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The role of an anti-inflammatory molecule AIM\/CD5L in gut ischemia\/reperfusion injury of male mice"],"prefix":"10.1186","volume":"31","author":[{"given":"Russell","family":"Hollis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaifeng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alok","family":"Jha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Tenet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monowar","family":"Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"issue":"2","key":"1385_CR1","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/nm.4012","volume":"22","author":"S Arai","year":"2016","unstructured":"Arai S, Kitada K, Yamazaki T, Takai R, Zhang X, Tsugawa Y, et al. 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This study was approved by the Institutional Animal Care and Use Committee of the Feinstein Institutes for Medical Research.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"321"}}