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 6

Exogenous IL-1β induces acute lung inflammation and lung tissue remodeling comparable to BLM.

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Exogenous IL-1β induces acute lung inflammation and lung tissue remodeli...
One i.n. rmIL-1β administration (1 μg per mouse, i.e., 0.05 mg/kg) induced acute neutrophil recruitment into BALF (A) and lung (B) in WT, TLR2/4–/–, and TNF-α–/– mice within 24 hours but was absent in IL-1R1–/– and MyD88–/– mice. rmIL-1β induced lung KC (C), IL-6 (D), and TARC (E) in WT, TLR2/4–/–, and TNF-α–/– mice but not in IL-1R1–/– and MyD88–/– mice. Pro-MMP-9 (103 kDa) (F) and TIMP-1 (G) activities were upregulated 24 hours after IL-1β instillation in the BALF of WT, TLR2/4–/–, and TNF-α–/– mice but not of IL-1R1–/– and MyD88–/– mice. Data represent mean values ± SD from 2 independent experiments (n = 4 mice per group; *P < 0.05; **P < 0.01).