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

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• 作者：Md Ashik Ullah ; MPharm^a ; ^b ; ^c ; Joana A. Revez ; BSci^c ; Zhixuan Loh ; B Biomed Sci^b ; Jennifer Simpson ; B Biomed Sci^b ; Vivian Zhang ; PhD^b ; Lisa Bain ; BSci^c ; Antiopi Varelias ; PhD^c ; Stefan Rose-John ; PhD^d ; Antje Blumenthal ; PhD^e ; Mark J. Smyth ; PhD^c ; ^f ; Geoffrey R. Hill ; MD^c ; ^g ; Maria B. Sukkar ; PhD^a ; ^h ; Manuel A.R. Ferreira ; PhD^c ; ^&lowast ; ; ^{manuel.ferreira@qimrberghofer.edu.au" class="auth_mail" title="E-mail the corresponding author} ; Simon Phipps ; PhD^b ; ^&lowast ; ; ^{s.phipps@uq.edu.au" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Tocilizumab ; MR16-1 ; sgp130-Fc ; eosinophils ; neutrophils ; IL-17 ; 纬未 T cell ; allergy ; endotype
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：136
• 期：4
• 页码：1065-1073
• 全文大小：1113 K

文摘

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 纬未 T cells. Anti–IL-6R, selective blockade of sIL-6R, or 纬未 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.