Role of Interleukin-17 and the Neutrophil in Asthma

Abstract

Recent clinical evidence shows that acute, severe exacerbations of asthma are associated with recruitment and activation of neutrophils in the airways. There is also experimental evidence from rodents that T-lymphocytes are involved in the recruitment of neutrophils following allergen challenge in sensitised airways. This review addresses the potential role of neutrophils and the cytokine interleukin-17 (IL-17) in severe asthma. IL-17 is produced and released as a free protein from T-lymphocytes of the memory (CD45RO+) subset. Evidence from rats in vivo suggests that IL-17 can recruit and activate neutrophils in the airways; the recruitment is mediated by the rat correlate to the neutrophil chemoattractant interleukin-8 (IL-8) macrophage inflammatory protein-2 (MIP-2). Endogenous peptidases modulate neutrophil recruitment by acting on NK-1 receptors in rat airways in vivo. Human bronchial epithelial cells in vitro respond to stimulation with IL-17 by increasing the production and release of the human neutrophil chemoattractant IL-8. This release of IL-8 is functionally significant; it causes neutrophil chemotaxis in vitro. Furthermore, this IL-8 release is sensitive to a glucocorticoid and is potentiated by the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-α) in vitro. In addition, IL-17 stimulates human bronchial epithelial cells in vitro to release the neutrophil-activating factor IL-6. This effect of IL-17 on IL-6, and IL-8 is in part mediated via mitogen-activated protein kinases. In conclusion, as indicated in rat airways in vivo and in human bronchial epithelial cells in vitro, IL-17 may constitute a link between the activation of certain T-lymphocytes and mobilisation of neutrophils in the airways, via induced release of C-X-C chemokines and tachykinins. Further studies are required to answer the question whether free, soluble IL-17 protein plays this role in the airways of patients with severe asthma.

Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: Important implications in asthma

“…Other potential roles of IL-17A in asthmatic airways might include the stimulation of mucus cell differentiation 25,41 and induction of chemokine and nitric oxide release. 22,23,30,42 Our study suggests that coexistence of T H 2 cytokines and IL-17A might have a significant effect on the pathogenesis of asthma by positively modulating the existing T (Fig 6, B and C). However, STAT6 nuclear translocation and IL-19 promoter binding were similar in IL-13-and IL-13/IL-17A-treated cells, despite the fact that IL-17A/IL-13-cotreated cells express much higher IL-19 compared with IL-13 alone.…”

“…This is the first demonstration that a T H 2 cytokine can coordinate with a proinflammatory cytokine, such as IL-17A, to potentiate a T H 2 response. 11,18,[28][29][30][31] This discovery emphasizes the uniqueness of epithelia-derived IL-19 in allergic diseases and suggests important roles for IL-13 and IL-17A in IL-19 regulation. [32][33][34] We hypothesize that airway epithelial IL-19 is induced by IL-17A and T H 2 cytokines, mainly IL-13, to further potentiate a T H 2-dominant response in a positive feedback manner in the context of allergic airway diseases, such as asthma.…”

“…[32][33][34][35][36] IL-17A also plays a role in human asthmatic patients and in airways of allergic animals. 18,28,30,[37][38][39] Studies have found that in patients with moderate-to-severe asthma, neutrophils are found to be more abundant than eosinophils in the bronchoalveolar lavage fluid. 30,31,40 IL-17A can promote neutrophil recruitment, which might contribute to certain asthmatic phenotypes characterized by both high neutrophil counts and IL-17A expression.…”

“…18,28,30,[37][38][39] Studies have found that in patients with moderate-to-severe asthma, neutrophils are found to be more abundant than eosinophils in the bronchoalveolar lavage fluid. 30,31,40 IL-17A can promote neutrophil recruitment, which might contribute to certain asthmatic phenotypes characterized by both high neutrophil counts and IL-17A expression. Other potential roles of IL-17A in asthmatic airways might include the stimulation of mucus cell differentiation 25,41 and induction of chemokine and nitric oxide release.…”

Mast cell–derived TNF can promote Th17 cell–dependent neutrophil recruitment in ovalbumin-challenged OTII mice

“…However, it is worth mentioning here that work in human subjects both has suggested that neutrophils may be potentially important contributors to airway pathology in certain subsets of patients with asthma, [41][42][43][44][45][46][47][48] and has identified IL-17 expression in the lungs of some subjects with this disorder. 32,[49][50][51][52][53] Therefore, it will be of interest to attempt to investigate whether the mechanisms that contribute to the mast cell-dependent enhancement of IL-17-dependent airway neutrophilia that have been revealed in our analyses of OTII mice have any bearing on the regulation of neutrophil recruitment that can occur in human asthma.…”