IL-6/Stat3-driven pulmonary inflammation, but not emphysema, is dependent on interleukin-17A in mice

Background and objectivePulmonary emphysema is linked to T cell-mediated autoimmune inflammation, although the pathogenic role of specific pro-inflammatory cytokines remains unclear. The Th17 type response, characterized by the production of the cytokine interleukin (IL)-17A, is modulated in part by the IL-6/signal transducer and activator of transcription (Stat)3 signalling axis and is associated with numerous autoimmune diseases. We therefore evaluated a causal role for IL-17A in the IL-6-driven gp130(F/F) mouse model for spontaneous pulmonary inflammation and emphysema. MethodsThe expression of Th17-related factors was quantified in the lungs of gp130(F/F) mice and emphysematous patients, and the degree of pulmonary inflammation and emphysema was measured in gp130(F/F):Il17a(-/-) mice by immunohistochemistry, stereology and respiratory mechanics. ResultsIn gp130(F/F) mice, lung gene expression of Il17a and other Th17-related factors was augmented compared with gp130(+/+) (wild-type), gp130(F/F):Il6(-/-) and gp130(F/F):Stat3(-/+) mice displaying normalized Stat3 activity and no lung inflammation. Importantly, genetic ablation of Il17a in gp130(F/F):Il17a(-/-) mice prevented lung inflammation; however, emphysema still developed. Additionally, messenger RNA expression of inflammatory genes Cxcl1, Cxcl2, Ccl2 and Tnf; as well as Il6 and the Stat3-target gene, Socs3, were upregulated in the lungs of gp130(F/F) mice compared with gp130(F/F):Il17a(-/-) and gp130(+/+) mice. Consistent with these findings, augmented IL17A expression was observed in emphysema patients presenting with inflammation compared with inflammation-free individuals. ConclusionsCollectively, our data suggest that the integration of IL-17A into the IL-6/Stat3 signalling axis mediates lung inflammation, but not emphysema, and that discrete targeting of IL-17A may alleviate pulmonary inflammatory-related diseases. Augmented IL-17A production in the lung participates in a feedback loop to promote IL-6-dependent hyperactivation of the Stat3 transcription factor, which is associated with pulmonary inflammation, but not emphysema. The selective integration of IL-17A into the IL-6/Stat3 signalling axis suggests that discrete targeting of IL-17A may alleviate pulmonary inflammatory-related diseases.