Role of IL-17 in asthma pathogenesis and its implications for the clinic

ABSTRACT

Introduction: Asthma is a respiratory disorder typically characterized by T-helper type 2 (Th2) inflammation that is mediated by cytokines, including IL-4, IL-5, and IL-13. Pathophysiologically, airway inflammation involving prominent eosinophilia, elevated IgE synthesis, airway hyperresponsiveness, mucus hypersecretion, and airway remodeling manifest clinically in patients as wheezing, breathlessness, chest tightness and episodic coughing. However, the Th2 paradigm falls short in interpreting the full spectrum of asthma severity.

Areas covered: Severe asthmatics represent a distinct phenotype with their mixed pattern of neutrophilic-eosinophilic infiltration and glucocorticoid insensitivity making them refractory to currently available therapies. Th17 cells and their signature cytokine, IL-17, have been implicated in the development of severe asthma. Here, we review the contribution of IL-17 in the pathological features of asthma, gathered from both human and animal studies published in Pubmed during the past 10 years, and briefly discuss the clinical implications of targeting IL-17 imbalance in asthmatic patients.

Expert opinion: With advancement in our understanding of the role of IL-17 in asthma pathology, it is clear that IL-17 is a targetable pathway which may lead to improvement in clinical symptoms of asthma. However, further elucidation of the complex interactions unfurled by IL-17 is essential in the empirical development of effective therapeutic options for refractory asthmatics.

KEYWORDS:

• Airway remodeling
• IL-17
• neutrophilic inflammation
• severe asthma
• steroid resistance
• Th17 cells

Article highlights

• Asthma is a classic example of a T cell-mediated disease with a largely Th2 bias but the Th2 paradigm falls short in interpreting the full spectrum of asthma severity.

• Severe asthma is a subset associated with a Th2-low phenotype and increased IL-17 production.

• Pro-inflammatory IL-6 together with anti-inflammatory TGF-β induce differentiation into Th17 cells indicating its capability to play dual regulatory roles in a contextual manner.

• In the airways, IL-17 induces a predominantly neutrophilic airway inflammation, mucus hypersecretion, goblet cell hyperplasia, myofibroblast differentiation, and airway smooth muscle proliferation.

• The precise role of IL-17 in asthmatic airway inflammation is still unclear as it positively as well as negatively regulates immune responses in experimental models of allergic airway disease.

• IL-17 promotes airway remodeling by activating epithelial cells, fibroblasts, and airway smooth muscle cells.

• Th17 cells and its cytokines are implicated in mechanisms of steroid resistance in asthma via induction of GR‐β expression and reduced apoptosis. Furthermore, glucocorticoid treatment also enhanced IL-17 production.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.