What is the role of interleukin-9 (IL-9) in asthma?

The Role of Interleukin-9 in Asthma

Interleukin-9 (IL-9) is a pleiotropic cytokine that plays a significant role in asthma pathogenesis through its effects on airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness, making it a potential therapeutic target for asthma treatment.

Key Functions of IL-9 in Asthma Pathophysiology

• IL-9 is primarily produced by the Th2 subset of T lymphocytes and contributes to the complex inflammatory cascade in asthma 1
• IL-9 regulates airway inflammation, mucus production, airway hyperresponsiveness, and airway fibrosis largely by increasing mast cell numbers and activity in the airways 1
• Transgenic mice with lung-selective expression of IL-9 demonstrate massive airway inflammation with eosinophils and lymphocytes as predominant infiltrating cell types 2
• IL-9 overexpression causes increased numbers of mast cells within the airway epithelium, epithelial cell hypertrophy, mucus accumulation, and increased subepithelial collagen deposition 2

IL-9 in Relation to Other Inflammatory Pathways

• IL-9 influences Th2 cell differentiation and contributes to both eosinophilic and non-eosinophilic asthma through its effects on mast cells 1
• In animal models, IL-9 transgenic mice display enhanced eosinophilic airway inflammation, elevated serum total IgE, and airway hyperresponsiveness following allergen challenge 3
• IL-9 blockade with anti-IL-9 antibodies significantly reduces airway hyperreactivity, eosinophil and lymphocyte counts in bronchoalveolar lavage fluid, and decreases IL-4, IL-5, and IL-13 production 4

Cellular Sources of IL-9

• Beyond Th2 cells, other CD4+ T cell subsets (Th9, Th17) and cells of innate immunity (mast cells, innate lymphoid cells type 2) can produce IL-9 5
• Th9 cells develop from naïve T cells in the presence of IL-4 and transforming growth factor beta (TGFβ) 5
• Type 2 innate lymphoid cells (ILC2s) can be important sources of IL-9, particularly in patients with comorbid type 2 diseases 6

IL-9 in Asthma Phenotypes

• IL-9's role may be particularly important in specific asthma phenotypes, similar to how other cytokines like IL-13 and IL-5 have been found to be relevant in specific subgroups 6
• The effectiveness of targeting IL-9 may depend on proper patient phenotyping, as has been demonstrated with other cytokine-targeted therapies 6
• Failure to pay attention to asthma subphenotypes might result in missing the therapeutic potential of IL-9 antagonism in specific patient populations 6

Therapeutic Implications

• Anti-IL-9 monoclonal antibodies (such as MEDI-528) have been studied in subjects with asthma 1
• Animal studies show that blockade of IL-9 may reduce airway inflammation and hyperresponsiveness, suggesting potential as a therapeutic strategy 4
• Like other cytokine-targeted therapies (anti-IL-13, anti-IL-5), the clinical efficacy of anti-IL-9 therapy may depend on selecting the appropriate asthma phenotype 6

Relationship to Other Inflammatory Mediators

• IL-9 works in concert with other cytokines in the inflammatory cascade, including IL-4, IL-5, and IL-13 4
• IL-9 blockade reduces the concentrations of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid in animal models 4
• The IL-9 pathway interacts with other inflammatory pathways, including those involving mast cells, which are important in both eosinophilic and non-eosinophilic asthma 1

Clinical Considerations and Pitfalls

• Similar to experiences with anti-IL-13 and anti-IL-5 therapies, the effectiveness of targeting IL-9 may be underestimated if not tested in properly phenotyped patient populations 6
• Approximately 50% of asthma patients have TH2-low asthma, highlighting the importance of identifying the right subpopulation for specific cytokine-targeted therapies 6
• The complex interplay between IL-9 and other inflammatory mediators necessitates careful consideration when developing therapeutic strategies targeting this pathway 5