Cigarette Smoke Induction of Interleukin-27/WSX-1 Regulates the Differentiation of Th1 and Th17 Cells in a Smoking Mouse Model of Emphysema

Abstract

IFN-γ-producing CD4+ T (Th1) cells and IL-17-producing CD4+ T (Th17) cells play a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immune regulation between Th1 and Th17 cells remains unclear. Previous studies have demonstrated that interleukin-27 (IL-27)/WSX-1 exerted pro- or anti-inflammatory effects in many acute inflammatory diseases by modulating T cell-mediated immune response, but little was known about its role in chronic inflammatory disease, especially in smoking-related lung diseases. Considering IL-27 is an important regulator in T lymphocytes immune responses and was found markedly increased in patients with COPD, we hypothesized that IL-27/WSX-1 may exert immuno-regulatory effects on the differentiation of Th1 and Th17 cells in smoking-related COPD. In this study, we aimed to evaluate the expression of IL-27 in patients with COPD and explore the role of IL-27/WSX-1 on Th1 and Th17 cells differentiation in a smoking mouse model of emphysema. We found that elevated expression of IL-27 was associated with increased proportion of Th1 cells and Th17 cells in patients with COPD and demonstrated parallel findings in cigarette smoke-exposed mice. In addition, cigarette smoke exposure upregulated the expression of IL-27R (WSX-1) by naive CD4+ T cells in mice. In vitro, IL-27 significantly augmented the secretion of IFN-γ by naive CD4+ T cells via a T-bet, p-STAT1, and p-STAT3-dependent manner, but inhibited the production of IL-17 by a ROR-γt and p-STAT1-dependent way. Furthermore, anti-IL27 treatment dramatically decreased the expression of IFN-γ-producing CD4+ T cells in cigarette smoke-exposed mice. These findings proposed that IL-27 has functions for promoting the expression of Th1 cells but inhibiting the expression of Th17 cells in vitro and IL-27 neutralization-attenuated Th1-mediated inflammation in vivo, suggesting targeting IL-27/WSX-1 may provide a new therapeutic approach for smoking-related COPD.

Enhanced Lung Inflammatory Response in Whole-body Compared to Nose-only Cigarette Smoke-exposed Mice

“…This corresponds to a type 2 mediated in ammation with a Th2 and Treg immune response which is surprising in the presence of IL-12 and IL-23. It stands to fact that this balance can later shift towards a full Th1/Th17 response with production of IFN-γ and IL-17, when CS exposure will induce more damage to the lungs [25,26,31] and might even persist after smoking cessation [32][33][34]. In human COPD, lymphocyte in ammation is mainly driven by a Th1 immune response with an enhanced IFN-γ production in both helper (CD4+) and cytotoxic (CD8+) T lymphocytes, that increased with COPD severity [35,36].…”

Erythromycin suppresses neutrophil extracellular traps in smoking-related chronic pulmonary inflammation

“…The severity of emphysema was assessed by the mean linear intercept (MLI). Single-cell suspensions from the lungs were prepared for flow cytometry as described previously 28 . All mice were purchased from the Guangxi Medical University Laboratory of Animal Centre and all animal experiments in this study were approved by the Laboratory Animal Ethics Committee of Guangxi Medical University (Nanning, China).…”

Th17 cytokines: novel potential therapeutic targets for COPD pathogenesis and exacerbations

“…The blood concentration of IL-17A, but not IL-22 increases with COPD severity and is negatively correlated with airflow limitation measured by forced expiratory volume in 1 s (FEV1). This is associated with higher proportions of Th17 cells and IL-17-producing CD8 + T-cells (Tc17) in the blood of COPD patients compared to healthy nonsmokers and healthy smokers; these numbers are related to airflow limitation severity [22,23,[26][27][28][29][30][31][32][33][34]. Interestingly, Th1 cells are elevated in blood from COPD and healthy smokers, but are not correlated with airway obstruction, suggesting that systemic Th17 inflammation may be more relevant in COPD pathophysiology [32,33].…”

“…IL-17A contributes to the development of lymphoid follicles via activation of CXCL12 and CXCL13 production [48,49], but IL-17A-positive cells are found in their periphery [38]. In contrast, ELISA IL-17A levels AE-COPD (n=21) > HNS (n=20) > S-COPD (n=23) SUN, 2016 [22] ELISA IL-17A levels AE-COPD (n=24) > S-COPD (n=26) = HS (n=23) WANG, 2015 [23] ELISA IL-17A levels S-COPD (n=65) > HS (n=35) = HNS (n=31) ¶ ZHANG, 2013 [24] ELISA IL-17A levels S-COPD (n=94) > HS (n=23) = HNS (n=22) § ZHANG, 2011 [83] ELISA IL-17A levels HC (n=31) > AE-COPD (n=73) ZOU, 2017 [25] ELISA IL-17A levels AE-COPD (n=60) > S-COPD (n=60) > HC (n=40) WANG, 2015 [23] ELISA IL-22 levels S-COPD (n=65) > HS (n=35) > HNS (n=31) ¶ ZHANG, 2013 [24] ELISA IL-22 levels S-COPD (n=94) = HS (n=23) > HNS (n=22) IMANI, 2016 [26] Flow cytometry IL-17A + CD4 + T-cells S-COPD (n=9) > HNS (n=8) LI, 2015 [27] Flow cytometry IL-17A + CD4 + T-cells S-COPD (n=21) = HS (n=21) > HNS (n=21) LI, 2014 [28] Flow cytometry IL-17A + CD4 + T-cells AE-COPD (n=32) > S-COPD (n=36) = HS (n=40) PAATS, 2012 [29] Flow cytometry IL-17A + and IL-22 + CD4 + T-cells S-COPD (n=30) = HNS (n=10) QIU, 2016 [30] Flow cytometry IL-17A + CD4 + T-cells S-COPD (n=38) > HS (n=20) = HNS (n=20) SOLLEIRO, 2015 [31] Flow cytometry IL-17A + CD4 + T-cells TS-COPD (n=24) > BE-COPD (n=17) > HNS (n=20) SUN, 2016 [22] Flow cytometry IL-17A + CD4 + T-cells AE-COPD (n=24) > S-COPD (n=26) = HS (n=23) VARGAS-ROJAS, 2011 [32] Flow cytometry IL-17A + CD4 + T-cells S-COPD (n=39) > HS (n=14) = HNS (n=15) WANG, 2015 [23] Flow cytometry IL-17A + CD4 + T-cells S-COPD (n=65) > HS (n=35) > HNS (n=31) ¶ ZHANG, 2016 [34] Flow cytometry IL-17A + CD4 + T-cells S-COPD (n=29) > HS (n=24) = HNS (n=27) PAATS, 2012 [29] Flow cytometry IL-17F + CD4 + T-cells S-COPD (n=30) > HNS (n=10) PAATS, 2012 [29] Flow cytometry IL-17A + , IL-17F + and IL-22…”