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However, the mechanisms by which CHI3L1 contributes to fibrogenesis remain undefined. Here, we showed that infiltrating monocyte-derived liver macrophages represent the main source of CHI3L1 in murine NASH. We developed a floxed CHI3L1 knock-out (KO) mouse to further study the cell-specific role of CHI3L1 ablation. Wildtype (WT) and myeloid cell-specific CHI3L1 KO mice (Cre<jats:sup>Lyz<\/jats:sup>) were challenged with a highly inflammatory and fibrotic dietary model of NASH by administering choline-deficient high-fat diet for 10\u00a0weeks. Macrophage accumulation and inflammatory cell recruitment were significantly ameliorated in the Cre<jats:sup>Lyz<\/jats:sup> group compared to WT (F4\/80 IHC <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, CD11b IHC <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Additionally, hepatic stellate cell (HSC) activation and fibrosis were strongly decreased in this group (\u03b1-SMA IHC <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, picrosirius red staining <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). In vitro studies were performed stimulating bone marrow derived macrophages, THP-1 (human monocytes) and LX2 (human HSCs) cells with recombinant CHI3L1 to dissect its relationship with fibrosis development. Results showed an important role of CHI3L1 regulating fibrosis-promoting factors by macrophages (<jats:italic>TGFB1 p<\/jats:italic>\u2009&lt;\u20090.05, <jats:italic>CTGF p<\/jats:italic>\u2009&lt;\u20090.01) while directly activating HSCs (<jats:italic>ACTA2 p<\/jats:italic>\u2009&lt;\u20090.01, <jats:italic>COL1A1 p<\/jats:italic>\u2009&lt;\u20090.01), involving IL13R\u03b12 as the potential mediator. Our findings uncovered a novel role of CHI3L1 derived from liver macrophages in NASH progression and identifies this protein as a potential anti-fibrotic therapeutic target.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Key messages<\/jats:title>\n                <jats:p><jats:list list-type=\"bullet\">\n                  <jats:list-item>\n                    <jats:p>We showed that CHI3L1 expression is increased in murine CDAA-HFAT diet NASH model, and that infiltrating macrophages are a key source of CHI3L1 production.<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>Myeloid cell-specific CreLyz CHI3L1 knock-out in mice fed with CDAA-HFAT diet improved the NASH phenotype, with significantly reduced accumulation of pro-inflammatory macrophages and neutrophils compared with WT group.<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>DEG and qPCR analysis of genes in CreLyz CHI3L1 knock-out mouse liver showed the mechanistic role of CHI3L1 in cellular chemotaxis.<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>HSC is directly activated by CHI3L1 via receptor IL13R\u03b12, leading to upregulation of collagen deposition and pro-fibrotic gene, TIMP-1 and TIMP-2 release in whole liver.<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>Direct stimulation of macrophages with CHI3L1 leads to upregulated expression of HSC-activation factors, suggesting its role in modulating macrophage-HSC crosstalk.<\/jats:p>\n                  <\/jats:list-item>\n                <\/jats:list><\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00109-023-02325-4","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T11:11:03Z","timestamp":1683803463000},"page":"813-828","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Myeloid-specific deletion of chitinase-3-like 1 protein ameliorates murine diet-induced steatohepatitis progression"],"prefix":"10.1007","volume":"101","author":[{"given":"Andrea D.","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Kui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Kaufmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Eun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Leszczynska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-3840","authenticated-orcid":false,"given":"Ariel E.","family":"Feldstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"issue":"12","key":"2325_CR1","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1001\/jama.2020.2298","volume":"323","author":"AC Sheka","year":"2020","unstructured":"Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S (2020) Nonalcoholic steatohepatitis: a review. 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