IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice
Top Cited Papers
Open Access
- 8 November 2007
- journal article
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 117 (12) , 3786-3799
- https://doi.org/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-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.Keywords
This publication has 95 references indexed in Scilit:
- Anakinra treatment in patients with adult-onset Still's disease is fast, effective, safe and steroid sparing: experience from an uncontrolled trialAnnals of the Rheumatic Diseases, 2007
- A pilot study of IL-1 inhibition by anakinra in acute goutArthritis Research & Therapy, 2007
- Gout: new insights into an old diseaseJournal of Clinical Investigation, 2006
- MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystalsJournal of Clinical Investigation, 2006
- Matrix Regulation of Lung Injury, Inflammation, and Repair: The Role of Innate ImmunityProceedings of the American Thoracic Society, 2006
- Pathogen Recognition and Innate ImmunityCell, 2006
- Cryopyrin activates the inflammasome in response to toxins and ATPNature, 2006
- NALPs: a novel protein family involved in inflammationNature Reviews Molecular Cell Biology, 2003
- Resistance of TNF/LTα double deficient mice to bleomycin‐induced fibrosisInternational Journal of Experimental Pathology, 1997
- Co‐expression of TNFα and IL‐1β in human acute pulmonary fibrotic diseases: An immunohistochemical analysisPathology International, 1996