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

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, Manuel A. R, Ferreira M. A. R. and Phipps, Simon (2015) Allergen-induced IL-6 trans-signaling activates γδ T cells to promote type 2 and type 17 airway inflammation. Journal of Allergy and Clinical Immunology, 136 4: 1065-1073. doi:10.1016/j.jaci.2015.02.032

Author 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, Manuel A. R
Ferreira M. A. R.
Phipps, Simon
Title Allergen-induced IL-6 trans-signaling activates γδ T cells to promote type 2 and type 17 airway inflammation
Journal name Journal of Allergy and Clinical Immunology   Check publisher's open access policy
ISSN 1097-6825
Publication date 2015-01-01
Sub-type Article (original research)
DOI 10.1016/j.jaci.2015.02.032
Open Access Status Not Open Access
Volume 136
Issue 4
Start page 1065
End page 1073
Total pages 9
Place of publication Philadelphia, United States
Publisher Mosby
Language eng
Formatted abstract
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 γδ T cells. Anti–IL-6R, selective blockade of sIL-6R, or γδ 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.
Keyword Tocilizumab
γδ T cell
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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