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Despite advances in understanding the pathogenic role of eCIRP in inflammatory diseases, novel therapeutic strategies to prevent its excessive inflammatory response are lacking. Milk fat globule-epidermal growth factor-VIII (MFG-E8) is critical for the opsonic clearance of apoptotic cells, but its potential involvement in the removal of eCIRP was previously unknown. Here, we report that MFG-E8 can strongly bind eCIRP to facilitate \u03b1v\u03b23-integrin-dependent internalization and lysosome-dependent degradation of MFG-E8\/eCIRP complexes, thereby attenuating excessive inflammation. Genetic disruption of MFG-E8 expression exaggerated sepsis-induced systemic accumulation of eCIRP and other cytokines, and consequently exacerbated sepsis-associated acute lung injury. In contrast, MFG-E8\u2013derived oligopeptide recapitulated its eCIRP binding properties, and significantly attenuated eCIRP-induced inflammation to confer protection against sepsis. Our findings suggest a novel therapeutic approach to attenuate eCIRP-induced inflammation to improve outcomes of lethal sepsis.<\/jats:p>","DOI":"10.1093\/jleuko\/qiad119","type":"journal-article","created":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T22:23:57Z","timestamp":1696026237000},"page":"385-400","source":"Crossref","is-referenced-by-count":14,"title":["A novel opsonic eCIRP inhibitor for lethal sepsis"],"prefix":"10.1093","volume":"115","author":[{"given":"Colleen P","family":"Nofi","sequence":"first","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research , 350 Community Drive, Manhasset, NY 11030 , United States"},{"name":"Elmezzi Graduate School of Molecular Medicine , 350 Community Drive, Manhasset, NY 11030 , United States"},{"name":"Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell , 500 Hofstra Blvd, Hempstead, NY 11549 , United 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States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M","family":"Prince","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research , 350 Community Drive, Manhasset, NY 11030 , United States"},{"name":"Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell , 500 Hofstra Blvd, Hempstead, NY 11549 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0211-9000","authenticated-orcid":false,"given":"Haichao","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research , 350 Community Drive, Manhasset, NY 11030 , United States"},{"name":"Elmezzi Graduate School of Molecular Medicine , 350 Community Drive, Manhasset, NY 11030 , United States"},{"name":"Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell , 500 Hofstra Blvd, Hempstead, NY 11549 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monowar","family":"Aziz","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research , 350 Community Drive, Manhasset, NY 11030 , United States"},{"name":"Elmezzi Graduate School of Molecular Medicine , 350 Community Drive, Manhasset, NY 11030 , United States"},{"name":"Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell , 500 Hofstra Blvd, Hempstead, NY 11549 , United States"},{"name":"Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell , 500 Hofstra Blvd, Hempstead, NY 11549 , United 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