Interleukin-17A is involved in development of spontaneous pulmonary emphysema caused by Toll-like receptor 4 mutation

Abstract

Aim: To explore the pathogenic role of Th17 cells and interleukin-17A (IL-17A)-associated signaling pathways in spontaneous pulmonary emphysema induced by a Toll-like receptor 4 mutant (TLR4 mut ). Methods: Lungs were obtained from wild-type (WT) or TLR4 mut mice that were treated with or without recombinant mouse IL-17A (1 μg·kg, ip) from the age of 3 weeks to 3 months. Pulmonary emphysema was determined using histology, immunochemistry, and biochemical analysis. T cell polarization was determined with flow cytometry, the levels of cytokines were measured using ELISA, and the levels of IL-17A-associated signaling molecules were detected using Western blot. Results: Compared to WT mice, 3 month-old TLR4 mut mice were characterized by significantly reduced infiltration of Th17 cells into lungs (2.49%±1.13% νs 5.26%±1.39%), and significantly reduced expression levels of IL-17A (3.66±0.99 pg/μg νs 10.67±1.65 pg/μg), IL-23 (12.43±1.28 pg/μg νs 28.71±2.57 pg/μg) and IL-6 (51.82±5.45 pg/μg νs 92.73±10.91 pg/μg) in bronchoalveolar lavage fluid. In addition, p38 MAPK phosphorylation and AP-1 expression were decreased to 27%±9% and 51%±8%, respectively, of that in WT mice. Treatment of TLR4 mut mice with IL-17A increased the infiltration of Th17 cells into lungs and expression levels of IL-17A, IL-6, and IL-23 in bronchoalveolar lavage fluid, attenuated MDA and apoptosis, and improved emphysema accompanied with increased phosphorylation of p38 MAPK and expression of AP-1. Conclusion: Th17 cells, in particular the cytokine IL-17A, play a crucial role in the pathogenesis of TLR4 mut -induced spontaneous pulmonary emphysema. Both of them are potential targets for therapeutic strategies for pulmonary emphysema.

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

“…oxidative stress, apoptosis) implicated in emphysema. For example, while IL‐17A can protect against oxidative stress‐associated emphysematous changes in TLR4‐deficient mice, IL‐17A appears to directly promote CS‐induced alveolar cell apoptosis in wild‐type mice . Regarding the latter, at least in the context of IL‐6‐induced alveolar cell apoptosis that is the primary pathological emphysematous process in gp130 F/F mice, our data presented here suggest that IL‐17A does not promote IL‐6‐induced cellular apoptosis.…”

Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response

“…IL-23-dependent Th17 cells can invade the target organ and promote the development of organ-specific autoimmune inflammation [41,42] . The current study demonstrated that DZ2002 treatment markedly reduced the Th17 population in NZB/W F 1 mice, accompanied by a comprehensive suppression of IL-17 production.…”

Effect of Toll-like receptor 4 deficiency on clinical severity and expression of Th1/Th2/Th17-associated cytokines in a murine model of experimental autoimmune neuritis

“…However, whether there is an association of Th17 cells or IL-17 cytokines with TLR4 in EAN remains poorly documented. Wang et al [18] found that IL-17A participated in development of spontaneous pulmonary emphysema which was caused by Toll-like receptor 4 mutation.…”

“…Wang et al . [ 18 ] found that IL-17A participated in development of spontaneous pulmonary emphysema which was caused by Toll-like receptor 4 mutation.…”