Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent

By M. Wilson, S. Madala, T. Ramalingam, B. Gochuico, I. Rosas, A. Cheever, TA Wynn. Journal of Experimental Medicine, 2010

730 citations recorded by the source corpus.

Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4+ and γδ+ T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a−/− mice confirmed an essential role for IL-17A. Mechanistically, using ifnγ−/−, il10−/−, il10−/−il12p40−/−, and il10−/−il17a−/− mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is suppressed by IL-10 and facilitated by IFN-γ and IL-12/23p40. BLM-induced IL-17A production was also TGF-β dependent, and recombinant IL-17A–mediated fibrosis required TGF-β, suggesting cooperative roles for IL-17A and TGF-β in the development of fibrosis. Finally, we show that fibrosis induced by IL-1β, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1β were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis.

Subfields: Immunology, Physiology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/b465e8fbffc53b39e998760e370fb2837523b6fc

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. TA Wynn
2. P. Murray
3. D. Sheppard
4. S. Friedman
5. Jeremy S. Duffield
6. R. Locksley
7. S. V. Van Dyken
8. R. Medzhitov

In Physiology

1. Jeremy S. Duffield
2. D. Sheppard
3. S. Friedman
4. TA Wynn

In Pulmonary and Respiratory Medicine

1. Jeremy S. Duffield
2. S. Friedman
3. P. Murray
4. D. Sheppard
5. S. Violette
6. TA Wynn

Citations in the corpus

• Therapy for Fibrotic Diseases: Nearing the Starting Line (2013, background): “IL-13, IL-17, and related cytokines are interesting potential targets for treatment for chronic fibrotic diseases.”
• Protective and pathogenic functions of macrophage subsets (2011, background): “IL-1β stimulates T H 17 cells to produce IL-17, which was identified as an important inducer of bleomycin-induced pulmonary fibrosis, a fibrotic disorder with characteristics that are similar to those of IP”
• Integrating mechanisms of pulmonary fibrosis (2011, background): “IL-17A is increased in the bronchoalveolar lavage (BAL) fluid of patients with IPF (Wilson et al., 2010).”