IL-17A enhances IL-13 activity by enhancing IL-13–induced signal transducer and activator of transcription 6 activation

Abstract

Background Increased IL-17A production has been associated with more severe asthma, however the mechanisms whereby IL-17A may contribute to IL-13-driven pathology in asthma remain unclear. Objective We sought to gain mechanistic insight into how IL-17A can influence IL-13-driven responses. Methods The effect of IL-17A on IL-13-induced airway hyperresponsiveness (AHR), gene expression, mucus hypersecretion, and airway inflammation was assessed using in vivo models of IL-13-induced lung pathology and in vitro culture of murine fibroblast cell lines and primary fibroblasts, and human epithelial cell lines or primary human epithelial cells exposed to IL-13, IL-17A, or IL-13 and IL-17A. Results Compared to mice given intratracheal IL-13 alone, those exposed to IL-13 and IL-17A displayed augmented AHR, mucus production, airway inflammation and IL-13-induced gene expression. In vitro, IL-17A enhanced IL-13-induced gene expression in asthma-relevant murine and human cells. In contrast to the exacerbating influence of IL-17A on IL-13-induced responses, co-exposure to IL-13 inhibited IL-17A-driven antimicrobial gene expression in vivo and in vitro. Mechanistically, in both primary human and murine cells, IL-17A-driven elevation of IL-13-induced gene expression was associated with enhanced IL-13-driven STAT6 activation. Conclusions Our data suggest that IL-17A contributes to asthma pathophysiology by increasing the capacity of IL-13 to activate intracellular signaling pathways such as STAT6. These data represent the first mechanistic explanation of how IL-17A may directly contribute to the pathogenesis of IL-13-driven pathology.

IL‐13 signaling through IL‐13 receptor α2 mediates airway epithelial wound repair

“…As baseline expression of IL-13Ra2 is lower relative to IL-13Ra1, and IL-13Ra2 is a high-affinity receptor, even modest up-regulation of protein expression in response to mechanical wounding and IL-13 exposure would still have biological effects and yield functional changes. Our findings are consistent with previous studies that demonstrate IL-13-induced up-regulation of IL-13Ra2 mRNA transcript (41,42). Other studies have also shown that IL-13Ra2 expression is tightly regulated in response to other injury signals, including viral antigens and viral response cytokines.…”

Short‐term high‐fat diet feeding protects from the development of experimental allergic asthma in mice

“…The mechanisms involved in the translocation of neutrophils from the lung tissue into the alveolar space are still incompletely understood. However, IL‐17, partly secreted by Th17 cells, is a known trigger of neutrophilic inflammation in experimental OVA‐induced and human allergic asthma, and Th17 immunity has been associated with the severity of allergic asthma, through a synergism of IL‐17 and IL‐13 . Interestingly, we observed a decreased T‐cell infiltration into the airways in HFD mice, together with a decreased frequency of pulmonary Th17 cells, which may explain the observed reduction in airway neutrophils.…”

“…However, IL-17, partly secreted by Th17 cells, is a known trigger of neutrophilic inflammation in experimental OVA-induced and human allergic asthma, 42 and Th17 immunity has been associated with the severity of allergic asthma, through a synergism of IL-17 and IL-13. 43,44 Interestingly, we observed a decreased T-cell infiltration into the airways in HFD mice, together with a decreased frequency of pulmonary Th17 cells, which may explain the observed reduction in airway neutrophils. Alternatively, obesity, in acute lung injury, suppresses neutrophil chemotaxis through the downregulation of chemotactic receptors such as CXCR2.…”

The role of interleukin-17 in tumor development and progression

“…The impact on mRNA metabolism also enables IL-17 to synergize with other cytokines such as TNF to amplify the inflammatory response (Chiricozzi et al, 2011). Interestingly, IL-17 has been shown to cooperate with a wide range of signaling activators, including IFN-γ, IL-13, TGF-β, and even microbial products (Fabre et al, 2014a;Hall et al, 2017;Kaiko et al, 2019;Teunissen et al, 1998;Verma et al, 2017). Such promiscuity is highly relevant but poorly understood in the context of intratumoral inflammation, which is usually driven by a myriad of factors and exhibits considerable heterogeneity, even among tumors of the same tissue origin.…”