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


OBJECTIVE
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.


CONCLUSIONS
Experimental asthma associated with both high IL-6 and high sIL-6R levels in the airways is attenuated by treatment with IL-6R inhibitors.
Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia; Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia; QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Md Ashik
MA
Ullah
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Joana A
JA
Revez
Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
Zhixuan
Z
Loh
Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
Jennifer
J
Simpson
Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
Vivian
V
Zhang
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Lisa
L
Bain
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Antiopi
A
Varelias
Department of Biochemistry, Christian-Albrechts-Universität of Kiel, Kiel, Germany.
Stefan
S
Rose-John
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
Antje
A
Blumenthal
QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Medicine, University of Queensland, Herston, Australia.
Mark J
MJ
Smyth
QIMR Berghofer Medical Research Institute, Brisbane, Australia; Department of Bone Marrow Transplantation, Royal Brisbane Hospital, Brisbane, Australia.
Geoffrey R
GR
Hill
Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia; School of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia.
Maria B
MB
Sukkar
QIMR Berghofer Medical Research Institute, Brisbane, Australia. Electronic address: manuel.ferreira@qimrberghofer.edu.au.
Manuel A R
MA
Ferreira
Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia. Electronic address: s.phipps@uq.edu.au.
Simon
S
Phipps
D000485:Allergens / Q000276:immunology / Q000633:toxicity; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D003058:Cockroaches / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D051379:Mice; D039981:Pyroglyphidae / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
D000485:Allergens; D015850:Interleukin-6; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019947:Receptors, Interleukin-6
IL-17; MR16-1; Tocilizumab; allergy; endotype; eosinophils; neutrophils; sgp130-Fc; γδ T cell