Abstract
Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD). Interleukin-17A (IL-17A) is a pivotal cytokine that regulates lung immunity and inflammation. The aim of the present study was to investigate how IL-17A regulates CS-induced lung inflammation in vivo. IL-17A knockout (KO) mice and neutralization of IL-17A in wild-type (WT) mice reduced macrophage and neutrophil recruitment and chemokine (C-C motif) ligand 2 (CCL2), CCL3 and matrix metalloproteinase (MMP)-12 mRNA expression in response to acute CS exposure. IL-17A expression was increased in non-obese diabetic (NOD) severe combined immunodeficiency SCID) mice with non-functional B- and T-cells over a 4-week CS exposure period, where macrophages accumulated to the same extent as in WT mice. Gene expression analysis by QPCR (quantitative real-time PCR) of isolated immune cell subsets detected increased levels of IL-17A transcript in macrophages, neutrophils and NK/NKT cells in the lungs of CS-exposed mice. In order to further explore the relative contribution of innate immune cellular sources, intracellular IL-17A staining was performed. In the present study, we demonstrate that CS exposure primes natural killer (NK), natural killer T (NKT) and γδ T-cells to produce more IL-17A protein and CS alone increased the frequency of IL17+ γδ T-cells in the lung, whereas IL-17A protein was not detected in macrophages and neutrophils. Our data suggest that activation of innate cellular sources of IL-17A is an essential mediator of macrophage accumulation in CS-exposed lungs. Targeting non-conventional T-cell sources of IL-17A may offer an alternative strategy to reduce pathogenic macrophages in COPD.
Highlights
Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD) and accounts for ∼85 % of cases in industrialized countries, but other environmental pollutants, especially biomass fuel smoke, are important causes in developing countries [1]
Deletion of IL-17A inhibits CS-induced bronchoalveolar lavage fluid (BALF) cellularity and expression of monocyte/macrophage chemokines In WT C57BL/6 mice exposed to CS generated from nine cigarettes per day for 4 days, there was a significant increase in the total number of cells (4.62 +− 0.29 × 105), neutrophils (4.10 +− 0.33 × 104) and macrophages (4.20 +− 0.29 × 105) in BALF (Figures 1A–1C) compared with sham-exposed mice (1.25 +− 0.20 × 105, 0.02 +− 0.010 × and 1.24 +− 0.20 × respectively; P < 0.05)
WT mice treated with CS had more IL-17A, CCL2, CCL3 and matrix metalloproteinase (MMP)-12 as measured by Quantitative real-time PCR (QPCR) in whole lung compared with sham-exposed WT mice (Figure 2)
Summary
Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD) and accounts for ∼85 % of cases in industrialized countries, but other environmental pollutants, especially biomass fuel smoke, are important causes in developing countries [1]. CS causes lung inflammation where macrophages and neutrophils are prominent, leading to oxidative stress, emphysema, small airways fibrosis, mucus hypersecretion and progressive airflow limitation [1] Both neutrophils and macrophage lineage cells are essential effectors in these processes. Interleukin (IL)-17A is increasingly recognized as a fundamentally important regulator of cellular immunity and is Abbreviations: Ab, antibody; APC, allophycocyanin; BALF, bronchoalveolar lavage fluid; CCL, C-C (motif) chemokine ligand; COPD, chronic obstructive pulmonary disease; CS, cigarette smoke; DMEM, Dulbecco’s modified Eagle’s medium; IL, interleukin; IL-17R, IL-17 receptor; KO, knockout; mAb, monoclonal antibody; MMP, matrix metalloproteinase; NK, natural killer; PE, phycoerythrin; QPCR, quantitative real-time PCR; TGF, transforming growth factor; Th17, T helper 17 cell; WT, wild-type
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