IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice
Pamela Gasse, … , Bernhard Ryffel, Isabelle Couillin
Pamela Gasse, … , Bernhard Ryffel, Isabelle Couillin
Published November 8, 2007
Citation Information: J Clin Invest. 2007;117(12):3786-3799. https://doi.org/10.1172/JCI32285.
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Research Article Pulmonology

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

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-1β 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-1β 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.

Authors

Pamela Gasse, Caroline Mary, Isabelle Guenon, Nicolas Noulin, Sabine Charron, Silvia Schnyder-Candrian, Bruno Schnyder, Shizuo Akira, Valérie F.J. Quesniaux, Vincent Lagente, Bernhard Ryffel, Isabelle Couillin

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Figure 5

Reduced pulmonary fibrosis in IL-1R1– and MyD88-deficient mice.

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Reduced pulmonary fibrosis in IL-1R1– and MyD88-deficient mice. Lung mic...
Lung microscopic sections showed extensive fibrotic areas at day 11 with collagen deposition in WT mice (B) and TLR2 and TLR4 double-deficient mice (C) treated with BLM (15 mg/kg i.n.) in comparison with saline control mice (A). Fibrosis was significantly reduced in IL-1R1–/– mice (D) and in MyD88–/– mice (E) treated with BLM. Chromotrope Aniline Blue staining; magnification, ×200; n = 8 mice). Pulmonary collagen content was increased in WT mice, but not in IL1-R1–/– mice (F), as determined by Sircol assay. The latent form of TGF-β1 was present in BALF from WT mice 7 days after BLM but was undetectable in BALF from MyD88- and IL-1R1–deficient mice as determined by ELISA assay (G). Data represent mean values ± SD from 3 independent experiments (n = 4 mice per group; *P < 0.05; **P < 0.01).