{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:28:39Z","timestamp":1792456119962,"version":"4.5.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Alveolar echinococcosis (AE), a severe zoonotic disease predominantly endemic to pastoral regions, is characterized by hepatic parasitic lesions caused by <jats:italic>Echinococcus multilocularis<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study investigated the role of T-cell immunoglobulin and mucin domain-4 (TIMD4\/Tim-4) in patients with hepatic AE. In total, 129 patients were enrolled from the First Affiliated Hospital of Xinjiang Medical University between 1 March 2018 and 1 March 2021. Histological, genetic, and serological tests were employed to evaluate Tim-4 and inflammatory cytokine expression. The liver immune microenvironment at the middle and late stages of mice infected with <jats:italic>E. multilocularis<\/jats:italic> was established <jats:italic>in vitro<\/jats:italic> to assess cytokine dynamics and liver fibrosis biomarkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Clinical analysis revealed the upregulation of Tim-4 within the hepatic lesions of patients with AE, with its expression spatially localized to macrophage-enriched regions and functionally linked to extracellular inflammatory modulation. Meanwhile, the liver tissues of the patients had characteristic pathological changes in the vesicles and progressive fibrotic remodeling, concurrent with a significant suppression of proinflammatory cytokine activity. Tim-4+ macrophages inhibited the release of proinflammatory cytokines at the middle and late stages of <jats:italic>E.\u00a0multilocularis<\/jats:italic> infection to maintain immune tolerance, and inhibition of Tim-4 expression may even reverse the level of liver fibrosis <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Tim-4 attenuated the predominant proinflammatory response, thereby facilitating immune evasion by <jats:italic>E. multilocularis<\/jats:italic>. Notably, inhibition of Tim-4 in macrophages not only restored the inflammatory balance but also significantly reversed hepatic fibrotic progression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1600686","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T05:47:11Z","timestamp":1750225631000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["TIM4+macrophages suppress the proinflammatory response to maintain the chronic alveolar echinococcosis infection"],"prefix":"10.3389","volume":"15","author":[{"given":"Liang","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maidinaimu","family":"Aibibula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinping","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengming","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4562","DOI":"10.4049\/jimmunol.1203035","article-title":"TIM-4 has dual function in the induction and effector phases of murine arthritis","volume":"191","author":"Abe","year":"2013","journal-title":"J. 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