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- Title
A novel opsonic eCIRP inhibitor for lethal sepsis.
- Authors
Nofi, Colleen P; Tan, Chuyi; Ma, Gaifeng; Kobritz, Molly; Prince, Jose M; Wang, Haichao; Aziz, Monowar; Wang, Ping
- Abstract
Sepsis is a life-threatening inflammatory condition partly orchestrated by the release of various damage-associated molecular patterns such as extracellular cold-inducible RNA-binding protein (eCIRP). 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 αvβ3-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–derived 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.
- Subjects
SEPSIS; MILKFAT; RNA-binding proteins; OLIGOPEPTIDES; GENE expression; LUNG injuries
- Publication
Journal of Leukocyte Biology, 2024, Vol 115, Issue 2, p385
- ISSN
0741-5400
- Publication type
Article
- DOI
10.1093/jleuko/qiad119