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However, the precise cellular and molecular mechanisms underlying this process are not yet completely elucidated. CARD9 is known to modulate the activation of the NF-\u03baB family of transcription factors during anti-pathogen immune responses, but its involvement in sterile APAP-induced hepatitis has not been heretofore studied. To investigate this, we employed an APAP-induced liver injury model, which simulates the initial toxic demise of hepatocytes, followed by innate immune activation. Our findings reveal that CARD9 expression within Kupffer cells exacerbates liver damage by amplifying the production of proinflammatory factors, which are known to play a pathological role in noninfectious conditions. Furthermore, our study identifies TREM2 receptors on Kupffer cells as capable of recognizing components released upon cell death and operating as upstream signaling receptors to orchestrate tissue damage during sterile inflammation.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf222","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T12:07:43Z","timestamp":1769515663000},"source":"Crossref","is-referenced-by-count":0,"title":["CARD9 orchestrates tissue damage in APAP-induced hepatitis via TREM2-mediated sensing cell death"],"prefix":"10.1093","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8824-7668","authenticated-orcid":false,"given":"Zaopeng","family":"Yang","sequence":"first","affiliation":[{"name":"Institute for Immunology and School of Basic Medical Sciences, Tsinghua University , Beijing, 100084,","place":["China"]},{"name":"Tsinghua-Peking Center for Life Sciences, Tsinghua University , Beijing, 100084,","place":["China"]},{"name":"Changping Laboratory , Beijing , 102206,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4420-3964","authenticated-orcid":false,"given":"Shiqi","family":"Li","sequence":"additional","affiliation":[{"name":"Institute for Immunology and School of Basic Medical Sciences, Tsinghua University , Beijing, 100084,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renlin","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute for Immunology and School of Basic Medical Sciences, Tsinghua University , Beijing, 100084,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1045-4917","authenticated-orcid":false,"given":"Zhanqi","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute for Immunology and School of Basic Medical Sciences, Tsinghua University , Beijing, 100084,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueqiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute for Immunology and School of Basic Medical Sciences, Tsinghua University , Beijing, 100084,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0956-3654","authenticated-orcid":false,"given":"Xin","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute for Immunology and School of Basic Medical Sciences, Tsinghua University , Beijing, 100084,","place":["China"]},{"name":"Tsinghua-Peking Center for Life Sciences, Tsinghua University , Beijing, 100084,","place":["China"]},{"name":"Changping Laboratory , Beijing , 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