Role of Th17 Cytokines in Airway Remodeling in Asthma and Therapy Perspectives

Abstract

Airway remodeling is a frequent pathological feature of severe asthma leading to permanent airway obstruction in up to 50% of cases and to respiratory disability. Although structural changes related to airway remodeling are well-characterized, immunological processes triggering and maintaining this phenomenon are still poorly understood. As a consequence, no biotherapy targeting cytokines are currently efficient to treat airway remodeling and only bronchial thermoplasty may have an effect on bronchial nerves and smooth muscles with uncertain clinical relevance. Th17 cytokines, including interleukin (IL)-17 and IL-22, play a role in neutrophilic inflammation in severe asthma and may be involved in airway remodeling. Indeed, IL-17 is increased in sputum from severe asthmatic patients, induces the expression of "profibrotic" cytokines by epithelial, endothelial cells and fibroblasts, and provokes human airway smooth muscle cell migration in in vitro studies. IL-22 is also increased in asthmatic samples, promotes myofibroblast differentiation, epithelial-mesenchymal transition and proliferation and migration of smooth muscle cells in vitro. Accordingly, we also found high levels of IL-17 and IL-22 in a mouse model of dog-allergen induced asthma characterized by a strong airway remodeling. Clinical trials found no effect of therapy targeting IL-17 in an unselected population of asthmatic patients but showed a potential benefit in a sub-population of patients exhibiting a high level of airway reversibility, suggesting a potential role on airway remodeling. Anti-IL-22 therapies have not been evaluated in asthma yet but were demonstrated efficient in severe atopic dermatitis including an effect on skin remodeling. In this review, we will address the role of Th17 cytokines in airway remodeling through data from in vitro, in vivo and translational studies, and examine the potential place of Th17-targeting therapies in the treatment of asthma with airway remodeling.

Keywords: Th17 inflammation; airway remodeling; asthma; interleukine-17; interleukine-22.

Figure 1

Th17 pathway. (Left) acquisition of Th17 differentiation. 1-IL-6 and TGFβ, and IL-1β promote RORγt expression and Th17 differentiation. 2-IL-6 and TGFβ induce IL-23R expression which allows IL-23 to stabilize Th17 differentiation. 3-Th17 differentiation also includes secretion of IL-21 which in turn enhances Th17 differentiation, acting as a positive feedback loop. 4- Secretion of IL-17 and IL-22 by Th17 cell. (Right) action of IL-17 and IL-22 on their respective receptors and activation of corresponding downstream pathways in an epithelial cell. 5- IL-22 binding protein (IL-22BP) regulates action of IL-22. 6-IL-22R activation induce Janus Kinase 1 (JAK) and Tyk2 associated kinases which lead to activation of transcription factor STAT3 by phosphorylation. 7-IL-17R binding by IL-17 activates SEFIR intracellular domain which activates ERK, MAPK, C-Jun N-terminal pathways, and transcription factor NF-κB.

Figure 2

IL-17 and IL-22 cooperate to induce features of airway remodeling in asthma. ECM: extracellular matrix. Pro-inflammatory effect: release of IL-17 and IL-22 by Th17 cells and ILC-3 induce expression of neutrophil-attractant chemokines by endothelial cells and enhance neutrophil recruitment and diapedesis. IL-17 and IL-22 also induce expression of neutrophil-attractant and neutrophil-activating chemokines by epithelial cells and smooth muscle cells which lead to local neutrophilic inflammation with release of proteolytic enzymes (elastase, metalloproteases). Epithelial alterations: IL-17 and IL-22 also increase production of mucus by goblet cells and promotes goblet cell hyperplasia. They also alter epithelial integrity by enhancing E/N-cadherin switch which leads to epithelial-mesenchymal transition. Smooth muscle alterations: IL-17 and IL-22 promote smooth muscle cell proliferation, migration, and contractility (only IL-17). Subepithelial fibrosis: IL-17 and IL-22 stimulate fibroblast proliferation and switch to pro-fibrotic phenotype and promote collagen production and deposition in ECM relsulting in thickening of basement membrane. IL-22 also promotes migration of myofibroblast in smooth muscle cell bundles which contributes to local fibrosis and smooth muscle contractility.