5:
IL33 Receptor Deficiency Leads To Steroid Resistant Asthma Due To TSLP-driven Increase In IL9+ILC2s And Mast Cells
Friday, March 2, 2018: 2:00 PM
S210C (Convention Center)
Mukesh Verma, PhD, , , , ,
RATIONALE: IL33 plays an important role in asthma. We examined the role of the IL33 receptor (ST2) in a mouse model of chronic asthma.

METHODS: We studied tripe allergen (dust mite, ragweed and Aspergillus)-induced 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 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 caused a reduction in IL13+ CD4 T cells, Foxp3+ Tregs and IL5+ ILC2s but unexpectedly, induced 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. AHR in ST2 KO mice was steroid resistant. An anti-TSLP antibody abrogated AHR, inflammation and mucus production in allergen-treated ST2 KO mice, which was associated with a reduction in IL9+ and IL13+ ILC2s in the lung.

CONCLUSIONS: IL33 receptor deficiency paradoxically increases TSLP production, which stimulates the emergence of IL9+ and IL13+ ILC2s and mast cells, and development of steroid-resistant asthma. An anti-TSLP antibody abrogates all features of asthma in this model and is likely to be beneficial in steroid-resistant asthma.