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

Publication date: Available online 10 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Mukesh Verma, Sucai Liu, Lidia Michalec, Anand Sripada, Magdalena M. Gorska, Rafeul Alam
BackgroundIL33 plays an important role in development of experimental asthma.ObjectiveTo study the role of the IL33 receptor (ST2) in persistence of asthma in a mouse model.MethodsWe 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.ResultsThe 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.ConclusionsGenetic 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.



http://ift.tt/2hrZJZA