Journal of Allergy and Clinical Immunology
Journal of Allergy and Clinical Immunology
5 years ago

Title: Experimental Asthma Persists in IL33 Receptor Knockout Mice Due to the Emergence of a TSLP-driven IL9+ and IL13+ ILC2 subpopulations

IL33 plays an important role in development of experimental asthma. Objective To study the role of the IL33 receptor (ST2) in persistence of asthma in a mouse model. Methods We studied allergen-induced experimental asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness (AHR) by flexivent, inflammatory indices by ELISA, histology and real-time PCR, and ILC2s in lung single cell preparations by flow cytometry. Results The AHR level was elevated in allergen-treated ST2 KO mice and was comparable to that from allergen-treated WT controls. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of experimental asthma in ST2 KO mice was associated with an increase in the level of TSLP, IL9 and IL13 but not IL5 in bronchoalveolar lavage (BAL). ST2 deletion expectedly caused a reduction in IL13+ CD4 T cells, Foxp3+ Tregs and IL5+ ILC2s. Unexpectedly, ST2 deletion led to an overall increase in ILCs (CD45+lin-CD25+ cells), IL13+ ILC2s, the emergence of a TSLP-R+ IL9+ ILC2 population and an increase in intraepithelial mast cells in the lung. An anti-TSLP antibody abrogated AHR, inflammation and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in ILCs, ILC2s, and IL9+ and IL13+ ILC2s in the lung. Conclusions Genetic deletion of the IL33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL9+ and IL13+ ILC2s and mast cells, and leads to the development of chronic experimental asthma. An anti-TSLP antibody abrogates all pathologic features of asthma in this model.

Publisher URL: www.sciencedirect.com/science

DOI: S0091674917317475

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