TY - JOUR T1 - IL-4Ra signaling is required for thymic stromal lymphopoietin (TSLP)-induced type 2 airway inflammation JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.congress-2021.OA2833 VL - 58 IS - suppl 65 SP - OA2833 AU - Subhashini Srivatsan AU - George Scott AU - Dylan Birchard AU - Jeanne Allinne AU - Li-Hong Ben AU - Andrew J Murphy AU - Matthew A Sleeman AU - Jamie M Orengo Y1 - 2021/09/05 UR - http://erj.ersjournals.com/content/58/suppl_65/OA2833.abstract N2 - Introduction: Inhibiting the IL-4/IL-13 pathway has shown clinical benefit in diseases with underlying type 2 (T2) signatures (atopic dermatitis (AD), asthma and chronic sinusitis with nasal polyposis and eosinophilic esophagitis). While TSLP is implicated as a driver of T2 inflammation, it is not ubiquitously involved as evidenced by efficacy of TSLP blockade in clinical studies in asthmatics, but not in AD patients.Aim: To determine unique contributions of IL-4/IL-13 and TSLP signaling to T2 lung inflammation.Methods: Intranasal delivery of TSLP plus ovalbumin (Ova) to WT and Il4ra KO mice, or IL-4 or IL-13 to WT and Tslp KO mice, to induce lung inflammation. WT mice, receiving prophylactic treatment (anti‐IL-4R⍺, anti-TSLP, isotype control or no antibody), were sensitized and challenged with Ova or exposed to house dust mite (HDM). Terminal serum and lung endpoints were captured.Results: Intranasal TSLP plus Ova delivery promoted hallmark features of T2 lung inflammation, including goblet cell metaplasia, lung tissue eosinophilia and elevated IgE, all of which were abrogated in Il4ra KO mice. Conversely, IL-4 or IL-13 administration promoted several of these T2 endpoints independently of TSLP signaling. Consistently, pathway blockade in two preclinical models (Ova-alum or HDM), demonstrated that IL-4R⍺ blockade protected mice from T2 lung inflammation more effectively than TSLP blockade.Conclusion: We show that TSLP regulates T2 airway inflammation by engaging IL-4R⍺ signaling, while IL-4R⍺ drives T2 inflammation independently of TSLP. Furthermore, in the context of T2 inflammation, our data highlight a central role of IL-4R⍺ signaling in maintaining airway health.FootnotesCite this article as: European Respiratory Journal 2021; 58: Suppl. 65, OA2833.This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only). ER -