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Pathogenic E. coli is not only the major etiological agent of enteric\/diarrheal disease and urinary tract infections, but also among the most common causes of sepsis and meningitis. Caspase-8 is known to regulate apoptotic and pyroptotic cell death in response to bacterial and viral infections. Here we demonstrate that caspase-8 plays a critical role in E. coli\u2013induced macrophage apoptosis in vitro and in regulating immune response and host death in vivo. Incubation of mouse bone marrow derived macrophages (BMDMs) with an E. coli K1 strain CE10 triggered robust cell death, which is independent of the NAIP\/NLRC4\/caspase-1\/GSDMD pathway. CE10 stimulation induced caspase-8 activation, and macrophages deficient in caspase-8 and RIPK3, but not RIPK3 alone, were protected from CE10-induced cell death. In an intraperitoneal injection sepsis model, E. coli\u2013induced IL-1\u03b2, TNF-\u03b1, and IL-6 production was markedly reduced in caspase-8\u2212\/\u2212\/RIPK3\u2212\/\u2212 mice, compared with RIPK3\u2212\/\u2212 or wild type mice. Accordingly, the survival rate was significantly improved in caspase-8\u2212\/\u2212\/RIPK3\u2212\/\u2212 mice. Moreover, caspase-8 deficiency attenuated CE10-induced NF-\u03baB activation and cytokine production in BMDMs. Together, our findings identify caspase-8 as a central mediator of E. coli-induced cell death, immune response, and establish its critical contribution to host mortality during E. coli infection.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag037","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:02:19Z","timestamp":1776902539000},"source":"Crossref","is-referenced-by-count":0,"title":["Caspase-8 mediates\n                    <i>E. coli<\/i>\n                    -induced cell death and innate immune responses"],"prefix":"10.1093","volume":"215","author":[{"given":"Zhuodong","family":"Chai","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University , College Station, TX,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University , College Station, TX,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University , College Station, TX,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University , College Station, TX,","place":["United 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