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 4

BLM-induced lung tissue remodeling is IL-1R1 and MyD88 dependent.

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BLM-induced lung tissue remodeling is IL-1R1 and MyD88 dependent. pro-MM...
pro-MMP-9 (99 kDa) and MMP-2 (71 kDa) activities in BALF were analyzed by zymography 1 and 11 days after administration of BLM (15 mg/kg i.n.). Pro-MMP-9 was upregulated in the BALF of WT mice 24 hours after BLM administration and returned to normal levels at day 11, whereas MMP-2 was upregulated only at day 11 after BLM administration (data not shown). (A) Pro-MMP-9 activity was not upregulated in the BALF of MyD88–/– mice and only partially in IL-1R1–/– mice 24 hours after BLM administration. (B) MMP-2 was upregulated by BLM in the BALF of WT mice, but less so in MyD88–/– and IL-1R1–/– mice on day 11. (C) TIMP-1 as an indicator of a fibrotic process was upregulated in the lungs of WT but not MyD88–/– or IL-1R1–/– mice at 24 hours after BLM administration (15 mg/kg). (D) TIMP-1 concentrations were also increased in TLR2 and TLR4 double-deficient mice. TIMP-1 levels were assessed by ELISA, and data represent mean values ± SD from 2 independent experiments (n = 4 mice per group; *P < 0.05; **P < 0.01).