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. Author manuscript; available in PMC: 2016 Jan 1.
Published in final edited form as: J Allergy Clin Immunol. 2014 Nov 11;135(1):290–291. doi: 10.1016/j.jaci.2014.09.037

β2-Agonist therapy may contribute to the air pollution and IL-6–associated risk of developing severe asthma with dual-positive TH2/TH17 cells

Sergio E Chiarella a, G R Scott Budinger b, Gökhan M Mutlu c
PMCID: PMC4386576  NIHMSID: NIHMS670007  PMID: 25445822

To the Editor

We read the recently published manuscript by Irvin et al1 with great interest. The authors identified 3 distinct subgroups of asthma based on CD4 T-cell analysis in bronchoalveolar lavage fluid: TH2predominant, TH2/TH17predominant, and TH2/TH17low. The TH2/TH17predominant subgroup was defined as patients with TH2-predominant asthma whose TH2 cells coexpress IL-17. Patients in this subgroup with increased numbers of dual-positive TH2/TH17 cells had significantly more airflow limitation and increased airway reactivity in response to methacholine challenge and higher numbers of eosinophils in their blood when compared with patients in the other subgroups. Furthermore, TH2/TH17 cells were also resistant to steroid-induced cell death.

In their discussion they proposed TH2 cells as the most likely precursors for TH2/TH17 cells.2 They speculated that environmental factors known to aggravate asthma, such as air pollution, might be responsible for the differentiation of TH2 cells into TH2/TH17 cells through their ability to induce IL-6, which induces differentiation of TH2/TH17 cells from TH2 cells.1–4 They suggested that patients with TH2-predominant asthma can switch their endotype to TH2/TH17-predominant asthma over time in the presence of increased IL-6 production because of recurrent respiratory tract infections or exposure to environmental toxicants, such as air pollution.1,3–5

We agree with the authors’ conclusion. In human subjects exposure to particulate matter (PM) air pollution is associated with impaired lung development, worsening lung function, and increased asthma exacerbations.6–9 Supporting the role of air pollution as a risk factor for the development of TH2/TH17-predominant asthma, we previously reported that mice exposed to PM air pollution have a dose-dependent lung inflammation characterized by the release of IL-6, which was the predominant proinflammatory cytokine in the lungs.10,11 We have recently published that the administration of β2-adrenergic agonists, such as formoterol, causes a further increase in IL-6 release after exposure to PM. Furthermore, administration of short-acting β2-adrenergic agonists, such as albuterol, augmented the PM-induced IL-6 release from primary human alveolar macrophages.12 In view of these results by Irvin et al1 and our recent findings about the effect of β2-adrenergic receptor stimulation on IL-6 release during exposure to air pollution, we speculate that increased β2-agonist therapy use in patients who reside in areas of higher levels of PM air pollution might contribute to the induction of TH2/TH17 cells.

Acknowledgments

Supported by National Institutes of Health grants R01 ES015024 (to G.M.M.) and R01 ES013995 (to G.R.S.B.).

Footnotes

Disclosure of potential conflict of interest: G. R. S. Budinger has received research support from the National Institutes of Health (NIH) and is Deputy Editor of the American Thoracic Society (ATS). G. M. Mutlu has received research support from the NIH and is Associate Editor of the ATS. S. Chiarella declares that he has no relevant conflicts of interest.

References

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