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PMID: 17992263 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice.

The Journal of clinical investigation ·Vol. 117 ·No. 12 ·2007-12-00 ·Pages 3786-99

Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, Schnyder B, Akira S, Quesniaux VF, Lagente V, Ryffel B, Couillin I

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.

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,metabolism Lymphokines/genetics,metabolism Mice Mice, Knockout Myeloid Differentiation Factor 88/genetics,metabolism Pneumonia/chemically induced,genetics,metabolism,pathology Pulmonary Fibrosis/chemically induced,metabolism,pathology Receptors, Interleukin-1 Type I/agonists,antagonists & inhibitors,genetics,metabolism Recombinant Proteins/pharmacology Respiratory Distress Syndrome/chemically induced,genetics,metabolism,pathology Sialoglycoproteins/genetics,metabolism Signal Transduction/drug effects,genetics Transplantation Chimera/genetics,metabolism
Chemicals
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
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Gasse Pamela
Laboratory of Molecular Immunology and Embryology, University of Orleans and CNRS, Orleans, France.
Mary Caroline
Guenon Isabelle
Noulin Nicolas
Charron Sabine
Schnyder-Candrian Silvia
Schnyder Bruno
Akira Shizuo
Quesniaux Valérie F J
Lagente Vincent
Ryffel Bernhard
Couillin Isabelle
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI32285
Published
2007-12-00
Pages
3786-99
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2066195
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI32285 PMC Full Text View journal details
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