NDLI: Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Content Provider	PubMed Central
Author	Deng, Jane C. Cheng, Genhong Newstead, Michael W. Zeng, Xianying Kobayashi, Koichi Flavell, Richard A. Standiford, Theodore J.
Copyright Year	2006
Abstract	Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a “deactivated” phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor–associated kinase–M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonas aeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M–deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M–/– animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M–/– animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.
Related Links	http://dx.doi.org/10.1172/jci28054
Starting Page	2532
File Format	PDF
ISSN	00219738
Journal	Journal of Clinical Investigation
Issue Number	9
Volume Number	116
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2006-08-01
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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