title: 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.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. jdeng@mednet.ucla.edu
authors.forename: Jane C
authors.initials: JC
authors.lastname: Deng
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Michael W
authors.initials: MW
authors.lastname: Newstead
authors.forename: Xianying
authors.initials: X
authors.lastname: Zeng
authors.forename: Koichi
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000818:Animals; D003114:Colony-Forming Units Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D011552:Pseudomonas Infections / Q000276:immunology; D018805:Sepsis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D017346:Protein Serine-Threonine Kinases