IL-1R1/MyD88 Signaling and the Inflammasome Are Essential in Pulmonary Inflammation and Fibrosis in Mice

J Clin Invest. 2007 Dec;117(12):3786-99. doi: 10.1172/JCI32285.

Abstract

The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1beta recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1beta production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / toxicity
  • Bleomycin / toxicity
  • Bone Marrow Transplantation
  • Chronic Disease
  • Disease Models, Animal
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Interleukin-1beta / pharmacology
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Lymphokines / genetics
  • Lymphokines / metabolism
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • Pneumonia / chemically induced
  • Pneumonia / genetics
  • Pneumonia / metabolism*
  • Pneumonia / pathology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Receptors, Interleukin-1 Type I / agonists
  • Receptors, Interleukin-1 Type I / antagonists & inhibitors
  • Receptors, Interleukin-1 Type I / genetics
  • Receptors, Interleukin-1 Type I / metabolism*
  • Recombinant Proteins / pharmacology
  • Respiratory Distress Syndrome, Adult / chemically induced
  • Respiratory Distress Syndrome, Adult / genetics
  • Respiratory Distress Syndrome, Adult / metabolism*
  • Respiratory Distress Syndrome, Adult / pathology
  • Sialoglycoproteins / genetics
  • Sialoglycoproteins / metabolism
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Transplantation Chimera / genetics
  • Transplantation Chimera / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Interleukin-8
  • Lymphokines
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Interleukin-1 Type I
  • Recombinant Proteins
  • Sialoglycoproteins
  • lymphotactin
  • Bleomycin