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

Background and objective Pulmonary emphysema is linked to T cell‐mediated autoimmune inflammation, although the pathogenic role of specific pro‐inflammatory cytokines remains unclear. The T h17 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 ( S tat)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. Methods The expression of T h17‐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. Results In gp130 F / F mice, lung gene expression of Il17a and other T h17‐related factors was augmented compared with gp130 +/+ (wild‐type), gp130 F / F  :  Il6 −/− and gp130 F / F  :  Stat3 −/+ mice displaying normalized S tat3 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 Tnfα ; as well as Il6 and the S tat3‐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. Conclusions Collectively, our data suggest that the integration of IL ‐ 17A into the IL ‐6/ S tat3 signalling axis mediates lung inflammation, but not emphysema, and that discrete targeting of IL ‐ 17A may alleviate pulmonary inflammatory‐related diseases.