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Background: Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and the progressive decline in lung function. Multiple TH2cytokines including IL-4 and IL-13 have been shown to contribute to lung remodeling and lung function decline in the pathogenesis of IPF. However, the mechanisms whereby Th2-cytokine polarized T cells exacerbates the severity of fibrotic lung disease remain undefined. Importantly, interleukin-31 (IL-31) is a newly identified cytokine produced by TH2 T cells but its role in pulmonary inflammation and fibrosis is unknown. Methods: We treated wildtype and IL-31RA -/mice with Bleomycin repetitively via the intradermal route for 4 weeks to induce lung fibrosis. We then assessed changes in lung function and histology. We performed total lung RNA-Seq analysis and RT-PCR to measure the expression of genes related to fibrosis. Also, we measured changes in IL-31 producing cells in the lungs and PBMCs of IPF patients and healthy controls. Results: The lack of IL-31 signaling did not alter inflammation and collagen staining during bleomycin-induced pulmonary fibrosis. Also, the loss of IL-31RA signaling had no effect on the production of TH1, TH2 or TH17 cytokines in the lungs. Notably, we observed a significant improvement in the lung function of IL-31RA -/mice compared to wildtype mice treated with bleomycin. Our studies using chimeric bone-marrow transfers suggest that IL-31 signaling in nonhematopoietic cells contributes to the lung function decline during bleomycin-induced pulmonary fibrosis. The percentage of IL-31 producing CD4 + T cells was greater in PBMCs of IPF patients compared to control subjects. Conclusion: Our findings indicate a critical role for IL-31/IL-31RA signaling in declining lung function during bleomycin-induced pulmonary fibrosis. Future efforts to target this signaling pathway may be beneficial in controlling the progression of IPF and have implications for preserving and improving lung function.

Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Multiple Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 TH2 T cells, but its signaling receptor called IL-31RA has been shown predominately expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31 signaling in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. However, the loss of IL-31RA signaling did not affect inflammation in the lungs. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including ECM- and epithelial cell-associated gene networks. Furthermore, the lungs of IPF showed an elevated expression of IL-31 when compared to control subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. In summary, therapeutic targeting of the IL-31-IL-31RA axis could be beneficial in pulmonary fibrosis and has translational benefits specifically by preventing collagen deposition and improving lung function.

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