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.

TGF-β, IL-1β, IL-6 levels and TGF-β/Smad pathway reactivity regulate the link between allergic diseases, cancer risk, and metabolic dysregulations

“…The pro-inflammatory role of TGF-β in established asthma may be related to asthma highly inflammatory environment that includes high concentrations of IL-6 and IL-21 ( 152 ), which in mice induce Th17 differentiation in the presence of low levels of TGF-β ( 31 , 153 ) (in human, the presence of IL-1β is also required ( 32 )). Th17 cytokines, including IL-17, play a role in neutrophilic inflammation in severe asthma ( 154 ) and IL-21is increased in human asthmatic airways ( 155 ). In the early stage of asthma, the concentrations of IL-6 and IL-21 are likely insufficient to induce Th17 differentiation.…”

The Anti-Inflammatory Peptide TnP Is a Candidate Molecule for Asthma Treatment

“…First, we demonstrated that the presence of an eosinophilic infiltrate in the interstitial, perivascular and peribronchiolar regions of the lung and high IgE/IgG1 levels may favor increased Ahr and the initiation of lung remodeling, leading to the production of pro-fibrotic Th2 cytokines or other mediators responsible for the greater deposition of ECM components, such as collagen. Furthermore, the concurrent neutrophilic infiltration of the lungs associated with interconnected mechanisms, such as IL-17A, IFN-γ and IgG2a, indicates that neutrophil-rich inflammation was also driven by Th1/Th17 cells [ 28 , 33 ], relevant in the context of remodeling.…”

Eosinophilic Airway Diseases: From Pathophysiological Mechanisms to Clinical Practice

“…Although the pathogenesis of type 2-low asthma is not completely elucidated, the following mechanisms have been suggested to play a role in this subtype of asthma: (i) type 1 (IFN-mediated) and type 3 (IL-17-mediated) immune pathways together with airway neutrophilia; (ii) pauci-granulocytic mechanisms; (iii) systemic inflammation associated with IL-6, obesity, and metabolic dysfunction [ 32 ]. In particular, murine models show that IL-17 contributes to neutrophilic airway inflammation, bronchial hyper-responsiveness, mucus hypersecretion, airway obstruction, and corticosteroid resistance [ 33 , 34 , 35 ]. In addition, levels of Th17-derived IL-17 in the airway and peripheral blood correlate with disease severity [ 34 , 36 ].…”