IL-17A–Producing γδ T and Th17 Lymphocytes Mediate Lung Inflammation but Not Fibrosis in Experimental Silicosis

Abstract

IL-17–producing T lymphocytes play a crucial role in inflammation, but their possible implication in fibrosis remains to be explored. In this study, we examined the involvement of these cells in a mouse model of lung inflammation and fibrosis induced by silica particles. Upregulation of IL-17A was associated with the development of experimental silicosis, but this response was markedly reduced in athymic, γδ T cell-deficient or CD4+ T cell-depleted mice. In addition, γδ T lymphocytes and CD4+ T cells, but not macrophages, neutrophils, NK cells or CD8 T cells, purified from the lungs of silicotic mice markedly expressed IL-17A. Depletion of alveolar macrophages or neutralization of IL-23 reduced upregulation of IL-17A in the lung of silicotic mice. IL-17R–deficient animals (IL-17R−/−) or IL-17A Ab neutralization, but not IL-22−/− mice, developed reduced neutrophil influx and injury during the early lung response to silica. However, chronic inflammation, fibrosis, and TGF-β expression induced by silica were not attenuated in the absence of IL-17R or -22 or after IL-17A Ab blockade. In conclusion, a rapid lung recruitment of IL-17A–producing T cells, mediated by macrophage-derived IL-23, is associated with experimental silicosis in mice. Although the acute alveolitis induced by silica is IL-17A dependent, this cytokine appears dispensable for the development of the late inflammatory and fibrotic lung responses to silica.

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

“…At higher concentrations and more long-term models, such as hypersensitivity pneumonitis, 24,41 IL-17 may lead to a more protracted inflammatory state. In shorter-term "single-hit" models, such as bleomycin and silica, 48 in which IL-17 production is limited, IL-17 may have a less inflammatory role. Furthermore, IL-17 is capable of inducing all three CXCR-3 family members (ie, CXCL9, CXCL10, and CXCL11) because they have transcription factor-binding patterns associated with IL-17-induced genes.…”

IL-17A Produced by Neutrophils Protects against Pneumonic Plague through Orchestrating IFN-γ–Activated Macrophage Programming

“…Infected lung injury causes production of IL-17-promoting cytokines, such as TGF-b, IL-6, TNF-a, and IL-1b, in the inflamed lung (1). In addition, Th1, Th17, and neutrophils are important in the pathogenesis of autoimmune inflammation (15)(16)(17). Recently, some studies have examined the function of IL-17 in innate immunity, including in infected lungs (18,19).…”

“…The number of bacteria in the inoculating dose was confirmed by plating. The LD 50 Preparation of bronchoalveolar lavage fluid and lung single-cell suspensions Bronchoalveolar lavage fluid (BALF) was collected and harvested as previously described (17). In brief, the trachea was exposed by producing a midline incision and then cannulated with a sterile 22-gauge Abbocath-T catheter.…”

Innate-like function of memory Th17 cells for enhancing endotoxin-induced acute lung inflammation through IL-22

“…Although IL-23 was initially thought to mediate the T h 17 response, it was later found that it regulated the terminal differentiation of committed T h 17 cells and their expansion, migration, survival and maintenance (41). Also, IL-23 was required for the recruitment of T h 17 cells and mediated lung inflammation, as shown in an experimental silicosis (42). Therefore, it is likely that both the neutralization and deficiency of IL-23 ameliorate the disease by affecting the T h 17 memory/effector response.…”