Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease

Abstract

Interleukin (IL)-17 is a T helper 17 cytokine implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Although IL-17A has a well-established role in murine pulmonary fibrosis models, its role in the tissue remodeling and fibrosis occurring in idiopathic pulmonary fibrosis (IPF) and RA-associated interstitial lung disease (RA-ILD) is not very well defined. To address this question, we utilized complimentary studies to determine responsiveness of human normal and pathogenic lung fibroblasts to IL-17A and used lung biopsies acquired from patients with IPF and RA-ILD to determine IL-17A receptor (IL-17RA) expression. Both normal and pathogenic IPF lung fibroblasts express functional IL-17RA and respond to IL-17A stimulation with cell proliferation, generation of extracellular matrix (ECM) proteins, and induction of myofibroblast transdifferentiation. Small interfering RNA (siRNA) silencing of IL-17RA attenuated this fibroblast response to IL-17A on ECM production. These fibroblast responses to IL-17A are dependent on NF-κB-mediated signaling. In addition, inhibiting Janus activated kinase (JAK) 2 by either siRNA or a selective pharmacological inhibitor, AZD1480—but not a JAK1/JAK3 selective inhibitor, tofacitinib—also significantly reduced this IL-17A-induced fibrogenic response. Lung biopsies of RA-ILD patients demonstrate significantly higher IL-17RA expression in areas of fibroblast accumulation and fibrosis, compared with either IPF or normal lung tissue. These observations support a direct role for IL-17A in lung fibrosis that may be particularly relevant in the context of RA-ILD.

Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease: Lights and Shadows

“…In SKG mice, tofacitinib significantly suppressed the progression of ILD compared to control, by increasing myeloid-derived suppressor cells and suppressing Th17 cells proliferation and differentiation [180]. On the contrary, in another in vitro study, the JAK2 inhibition, but not the selective JAK1/JAK3 pathway, significantly reduced IL-17A-induced fibrogenic response in RA-ILD patients [181].…”

DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis

“…They suggest that the cytosolic DROSHA potentially alters the function depending on the interaction with partners such as substrate RNAs or regulatory mechanisms [100,101]. Additionally, Ye et al showed that E3 ubiquitin-protein ligase Mdm2 directly interacts with DROSHA [102]. Its interaction induces the ubiquitination of DROSHA, which causes the degradation of DROSHA protein [103].…”

“…The activation of these immune receptors could be protective or harmful events, which is determined by the type of DAMP and DAMP-related specific receptor. In IPF, the role of DAMPs has been investigated in IL-17A receptor (IL-17RA)-mediated NF-kB signaling and the role of high mobility group box 1 (HMGB1) during inflammation and fibrosis [102,105]. IL-17A stimulates proliferation and survival of airway smooth muscle cells via the activation of IL-17RA [106].…”

“…IL-17A stimulates proliferation and survival of airway smooth muscle cells via the activation of IL-17RA [106]. The stimulation of IL-17RA leads to changes to various cellular pathways including cell proliferation, myofibroblast differentiation, and the production of extracellular matrix (ECM) proteins [102]. The levels of HMGB1 in BAL were increased in patients with IPF compared the control [105].…”

Battling IL-17, the troublemaker in alcohol-induced hepatocellular carcinoma

“…7Consequently, SREBP1/2 activation leads to the augmented production and accumulation of fatty acids and cholesterol in hepatocytes: a hallmark of steatosis and the high energy demands of tumor progression.Recently, several studies on immune-related diseases including inflammation-driven cancers, lung and liver fibrosis, non-alcoholic steatohepatitis (NASH) and NASH-induced HCC have highlighted the role of the interleukin 17A (IL-17A) signaling pathway. [8][9][10][11][12] However, the underlying mechanisms underpinning a role for IL-17A in ALD and ALD-driven cancer were still unknown. IL-17A is a soluble pro-inflammatory cytokine mainly produced by T helper 17 (Th17) cells, in response to their stimulation by IL-6 and IL-23.…”