Cigarette Smoke-Induced Lymphoid Neogenesis in COPD Involves IL-17/RANKL Pathway

• Published in: Frontiers in immunology Vol. 11; p. 588522
• Main Authors: Xiong, Jing, Zhou, Lu, Tian, Jieyu, Yang, Xia, Li, Yunsong, Jin, Rong, Le, Yanqing, Rao, Yafei, Sun, Yongchang
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 05.02.2021
• Subjects: Animals; B-Lymphocytes - immunology; Chemokine CXCL13 - immunology; chronic obstructive pulmonary disease; Dendritic Cells - immunology; Female; Humans; Immunology; interleukin 17; Interleukin-17 - genetics; Interleukin-17 - immunology; Lung - immunology; lymphoid follicles; Lymphoid Tissue - immunology; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nicotiana; Pulmonary Disease, Chronic Obstructive - immunology; RANK; RANK Ligand - immunology; receptor activator of nuclear factor-κB ligand; Signal Transduction; Smoke - adverse effects; Smoking - immunology; RANK; lymphoid follicles; receptor activator of nuclear factor-κB ligand; interleukin 17; chronic obstructive pulmonary disease
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.588522

IL-17 is critical in lung lymphoid neogenesis in COPD, but the cellular and molecular mechanisms remain to be elucidated. Receptor activator of nuclear factor-κB ligand (RANKL) functions in lymphoid follicle formation in other organs, whether it is involved in IL-17A-dependent lymphoid neogenesis in COPD is unknown. To elucidate the expression and functional role of IL-17A/RANKL pathway in COPD. We first quantified and localized RANKL, its receptor RANK and IL-17A in lungs of patients with COPD, smokers and non-smokers. Next, IL-17A and wild-type (WT) mice were exposed to air or cigarette smoke (CS) for 24 weeks, and lung lymphoid follicles and RANKL-RANK expression were measured. Lastly, we studied the biological function of RANKL pertaining to lymphoid neogenesis. We found that the expressions of RANKL-RANK and IL-17A, together with lymphoid follicles, were increased in lung tissues from patients with COPD. In WT mice exposed to CS, RANKL-RANK expressions were prominent in lung lymphoid follicles, which were absent in IL-17A mice exposed to CS. In the lymphoid follicles, RANKL cells were identified mostly as B cells and RANK was localized in dendritic cells (DCs). IL-17A increased the expressions of RANKL in B cells and RANK in DCs, which in turn responded to RANKL stimulation by upregulation of CXCL13. Altogether, these results suggest that B lymphocyte RANKL pathway is involved in IL-17A-dependent lymphoid neogenesis in COPD.