Blockade of Interplay between IL-17A and Endoplasmic Reticulum Stress Attenuates LPS-Induced Lung Injury

• Published in: Theranostics Vol. 5; no. 12; pp. 1343 - 1362
• Main Authors: Kim, So Ri, Kim, Hee Jung, Kim, Dong Im, Lee, Kyung Bae, Park, Hae Jin, Jeong, Jae Seok, Cho, Seong Ho, Lee, Yong Chul
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2015
• Subjects: Animals; Cells, Cultured; Endoplasmic Reticulum Stress; Epithelial Cells - drug effects; Epithelial Cells - physiology; Humans; Interleukin-17 - metabolism; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - toxicity; Lung - pathology; Lung Injury - chemically induced; Mice, Inbred C57BL; Phenylbutyrates - administration & dosage; Research Paper; ER stress; IL-17A; epithelial cell; inflammation; acute lung injury; LPS
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.11685

IL-17 is a cytokine mainly from IL-17-producing T cells, which are one of subsets of CD4+ T cells and play a role in adaptive immune system. Recent studies have demonstrated that IL-17A can act rapidly as an innate immune responder during infection before the onset of its classic adaptive immune response. This role of IL-17A in innate immune response is implicated in lipopolysaccharide (LPS)-induced lung inflammation. Very recently, we have reported that endoplasmic reticulum (ER) stress is involved in LPS-induced lung inflammation in vivo and in vitro. This study aimed to elucidate the role of IL-17A in LPS-induced lung injury, focusing on the link with ER stress. We treated a murine model of LPS-induced lung injury with IL-17A neutralizing antibody and 4-phenylbutyrate (4-PBA), a representative ER stress inhibitor. In addition, we evaluated the effects of IL-17A on ER stress in LPS-stimulated bronchial epithelial cells. Our results showed that inhibition of IL-17A decreased LPS-induced pulmonary neutrophilia, vascular leakage, nuclear translocation of nuclear factor-κB (NF-κB), infiltration of dendritic cells, increased expression of Toll-like receptor 4 (TLR4), activation of NLRP3 inflammasome, and increased ER stress in the lung. 4-PBA or TAK-242, a TLR4 inhibitor attenuated expression of IL-17A thereby improving LPS-induced lung inflammation. Intriguingly, we observed that stimulation with LPS increased expression of IL-17A in airway epithelial cells and co-stimulation with IL-17A further increased ER stress and NF-κB activation. This study indicates that the interrelationship between IL-17A and ER stress plays an important role in LPS-induced injury showing a positive feedback in airway epithelial cells and suggests that targeting their interaction can be a potential therapeutic approach to overcome one of severe refractory pulmonary disorders.