Allergen-induced IL-6 trans-signaling activates gamma delta T cells to promote type 2 and type 17 airway inflammation

作者：Ullah Md Ashik; Revez Joana A; Loh Zhixuan; Simpson Jennifer; Zhang Vivian; Bain Lisa; Varelias Antiopi; Rose John Stefan; Blumenthal Antje; Smyth Mark J; Hill Geoffrey R; Sukkar Maria B; Ferreira Manuel A R; Phipps Simon^*

来源：Journal of Allergy and Clinical Immunology, 2015, 136(4): 1065-1073.

DOI：10.1016/j.jaci.2015.02.032

• Tocilizumab
• MR16-1
• sgp130-Fc
• eosinophils
• neutrophils
• IL-17
• gamma delta T cell
• allergy
• endotype

Background: A variant in the IL-6 receptor (IL-6R) gene increases asthma risk and is predicted to decrease IL-6 classic signaling and increase IL-6 trans-signaling. This suggests that inhibition of IL-6 trans-signaling, but not classic signaling, might suppress allergic airway inflammation.
Objectives: We sought to determine whether IL-6 signaling contributes to (1) acute experimental asthma induced by clinically relevant allergens and (2) variation in asthma clinical phenotypes in asthmatic patients.
Methods: Mice were sensitized to house dust mite (HDM) or cockroach at day 0, treated with IL-6R inhibitors at day 13, and challenged with the same allergen at days 14 to 17. End points were measured 3 hours after the final challenge. IL-6 and soluble IL-6 receptor (sIL-6R) expression in induced sputum of asthmatic patients was correlated with asthma clinical phenotypes.
Results: Both HDM and cockroach induced a type 2/type 17 cytokine profile and mixed granulocytic inflammation in the airways. Both allergens increased IL-6 expression in the airways, but only cockroach induced sIL-6R expression. Therefore HDM challenge promoted IL-6 classic signaling but not trans-signaling; in this model treatment with anti-IL-6R did not suppress airway inflammation. In contrast, cockroach-induced inflammation involved activation of IL-6 trans-signaling and production of IL-17A by gamma delta T cells. Anti-IL-6R, selective blockade of sIL-6R, or gamma delta T-cell deficiency significantly attenuated cockroach-induced inflammation. Asthmatic patients with high airway IL-6 and sIL-6R levels were enriched for the neutrophilic and mixed granulocytic subtypes.
Conclusion: Experimental asthma associated with both high IL-6 and high sIL-6R levels in the airways is attenuated by treatment with IL-6R inhibitors.

• 出版日期2015-10
• 单位河北医科大学