Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. 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 IL-31RA is primarily 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-31RA deficiency 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. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including extracellular matrix and epithelial cell-associated gene networks. Furthermore, the lungs of human IPF showed an elevated expression of IL-31 when compared to healthy 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. Thus, therapeutic targeting the IL-31-IL-31RA axis may prevent collagen deposition, improve lung function, and have therapeutic potential in pulmonary fibrosis.
Highlights
Pulmonary fibrosis is a chronic heterogeneous lung disease characterized by an uncontrolled injury and repair process in the lung parenchyma
To further evaluate collagen deposition, the level of hydroxyproline was quantified in the lungs of IL-31 receptor A (IL-31RA) knockout mice and wildtype mice treated with bleomycin or saline
Both wildtype and IL-31RA knockout mice treated with bleomycin had increased expression of lung hydroxyproline compared with saline-treated mice
Summary
Pulmonary fibrosis is a chronic heterogeneous lung disease characterized by an uncontrolled injury and repair process in the lung parenchyma. This process includes excessive deposition of collagen and extracellular matrix (ECM) protein components in the distal areas of the lung [1, 2]. Patients with severe fibrotic lung diseases including idiopathic pulmonary fibrosis (IPF) develop irreversible. The development of fibrotic lesions, is regulated by signaling pathways that are driven by multiple pro-fibrotic growth factors, including TGF-β, TGF-α, CTGF, and cytokines such as IL-1β, IL-17, IL-4, and IL-13 [6,7,8]. IL-4 and IL-13 signal through a type II IL-4 receptor alpha (IL-4Rα); this receptor is expressed in multiple cell types, including macrophages, epithelial cells, and fibroblasts [9]
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