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

J Clin Invest. 2006 Sep;116(9):2532-42. doi: 10.1172/JCI28054. Epub 2006 Aug 17.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Colony-Forming Units Assay
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Immunity, Innate*
  • Interleukin-1 Receptor-Associated Kinases
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lung / enzymology
  • Lung / immunology*
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Models, Animal
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism
  • Pseudomonas Infections / immunology
  • Sepsis / immunology*
  • Sepsis / pathology
  • Sepsis / prevention & control

Substances

  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • IRAK3 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Irak3 protein, mouse
  • Protein-Serine-Threonine Kinases