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However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Mice were fasted overnight before intraperitoneally (\n                      <jats:italic>i.p.<\/jats:italic>\n                      ) injected with APAP at a dose of 210 mg\/kg for male mice and 325 mg\/kg for female mice. Platelets adherent to Kupffer cells were determined in both mice and patients overdosed with APAP. The impact of \u03b1-chitinase 3-like-1 (\u03b1-Chi3l1) on alleviation of AILI was determined in a therapeutic setting, and liver injury was analyzed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      The present study unveiled a critical role of Chi3l1 in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice,\n                      <jats:italic>Chil1<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of\n                      <jats:italic>Cd44<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in\n                      <jats:italic>Chil1<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in\n                      <jats:italic>Chil1<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice, but not in\n                      <jats:italic>Cd44<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>We uncovered the Chi3l1\/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:<\/jats:title>\n                    <jats:p>ZS received funding from NSFC (32071129). FWL received funding from NIH (GM123261). ALFSG received funding from NIDDK (DK 058369). ZA received funding from CPRIT (RP150551 and RP190561) and the Welch Foundation (AU-0042\u201320030616). CJ received funding from NIH (DK122708, DK109574, DK121330, and DK122796) and support from a University of Texas System Translational STARs award. Portions of this work were supported with resources and the use of facilities of the Michael E. DeBakey VA Medical Center and funding from Department of Veterans Affairs I01 BX002551 (Equipment, Personnel, Supplies). The contents do not represent the views of the US Department of Veterans Affairs or the US Government.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7554\/elife.68571","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T08:01:24Z","timestamp":1623312084000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.68571","source":"Crossref","is-referenced-by-count":47,"title":["Chitinase 3-like-1 contributes to acetaminophen-induced liver injury by promoting hepatic platelet recruitment"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5064-1023","authenticated-orcid":true,"given":"Zhao","family":"Shan","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States"},{"name":"Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leike","family":"Li","sequence":"additional","affiliation":[{"name":"Texas Therapeutics Institute, UTHealth McGovern Medical School, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance Lynn","family":"Atkins","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8144-1515","authenticated-orcid":true,"given":"Yankai","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongmin","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas F","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, UTHealth McGovern Medical School, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dechun","family":"Feng","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Gui","sequence":"additional","affiliation":[{"name":"Texas Therapeutics Institute, UTHealth McGovern Medical School, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Texas Therapeutics Institute, UTHealth McGovern Medical School, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun Geun","family":"Lee","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology, Brown University, Providence, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack A","family":"Elias","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology, Brown University, Providence, United States"},{"name":"Division of Medicine and Biological Sciences, Warren Alpert School of Medicine, Brown University, Providence, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Med School, Dallas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Gao","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fong Wilson","family":"Lam","sequence":"additional","affiliation":[{"name":"Division of Pediatric Critical Care Medicine, Baylor College of Medicine, Houston, United States"},{"name":"Center for Translation Research on Inflammatory Diseases, Michael E. 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