Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M
Jane C. Deng, Genhong Cheng, Michael W. Newstead, Xianying Zeng, Koichi Kobayashi, Richard A. Flavell, Theodore J. Standiford
Jane C. Deng, Genhong Cheng, Michael W. Newstead, Xianying Zeng, Koichi Kobayashi, Richard A. Flavell, Theodore J. Standiford
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Research Article Immunology

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

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 Pseudomonasaeruginosa. 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.

Authors

Jane C. Deng, Genhong Cheng, Michael W. Newstead, Xianying Zeng, Koichi Kobayashi, Richard A. Flavell, Theodore J. Standiford

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Figure 1

Effect of abdominal sepsis on survival following secondary i.t. Pseudomonas challenge (A) and AM cytokine production in response to LPS (B).

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Effect of abdominal sepsis on survival following seco...
(A) Wild-type C57BL/6 mice underwent either CLP with a 26-gauge needle or sham surgery. Twenty-four hours later, mice were administered i.t. P. aeruginosa (PA) at the indicated doses and monitored for 10 days after challenge for survival. *P < 0.01; **P < 0.001 compared with CLP; n = 10/group; data representative of experiments performed in duplicate. (B) At 24 hours following CLP or sham surgery, mice were sacrificed for the isolation of AMs by BAL. AMs were adherence purified and then stimulated ex vivo with LPS (1 μg/ml) in media or with media alone (unstimulated) for 16 hours. Cell supernatants were collected for determination of TNF-α and IL-12p70 levels by ELISA. #P < 0.05; ##P < 0.01 as compared with corresponding sham; n = 5/group; experiments were performed in duplicate.