posted on 2014-12-22, 15:51authored byDavid J. Jackson, Heidi Makrinioti, Batika M. J. Rana, Betty W. H. Shamji, Maria-Belen Trujillo-Torralbo, Joseph Footitt, Jerico del-Rosario, Aurica G. Telcian, Alexandra Nikonova, Jie Zhu, Julia Aniscenko, Leila Gogsadze, Eteri Bakhsoliani, Stephanie Traub, Jaideep Dhariwal, James Porter, Duncan Hunt, Toby Hunt, Trevor Hunt, Luminita A. Stanciu, Musa Khaitov, Nathan W. Bartlett, Michael R. Edwards, Onn Min Kon, Patrick Mallia, Nikolaos G. Papadopoulos, Cezmi A. Akdis, John Westwick, Matthew J. Edwards, David J. Cousins, Ross P. Walton, Sebastian L. Johnston
Rationale:
Rhinoviruses are the major cause of asthma
exacerbations; however, its underlying mechanisms are poorly
understood. We hypothesized that the epithelial cell–derived
cytokine IL-33 plays a central role in exacerbation pathogenesis
through augmentation of type 2 inflammation.
Objectives:
To assess whether rhinovirus induces a type 2
inflammatory response in asthma
in vivo
and to define a role for IL-33
in this pathway.
Methods:
We used a human experimental model of rhinovirus
infection and novel airway sampling techniques to measure IL-4, IL-5,
IL-13, and IL-33 levels in the asthmatic and healthy airways during
a rhinovirus infection. Additionally, we cultured human T cells and type
2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirus-
infected bronchial epithelial cells (BECs) to assess type 2 cytokine
production in the presence or absence of IL-33 receptor blockade.
Measurements and Main Results:
IL-4, IL-5, IL-13, and IL-33 are
all induced by rhinovirus in the asthmatic airway in vivo and relate to
exacerbation severity. Further, induction of IL-33 correlates with
viral load and IL-5 and IL-13 levels. Rhinovirus infection of human
primary BECs induced IL-33, and culture of human T cells and ILC2s
with supernatants of rhinovirus-infected BECs strongly induced
type 2 cytokines. This induction was entirely dependent on IL-33.
Conclusions:
IL-33 and type 2 cytokines are induced during
a rhinovirus-induced asthma exacerbation in vivo. Virus-induced
IL-33 and IL-33
–
responsive T cells and ILC2s are key mechanistic
links between viral infection and exacerbation of asthma. IL-33
inhibition is a novel therapeutic approach for asthma exacerbations.
History
Citation
American Journal of Respiratory and Critical Care Medicine, 190 (12), 2014, pp. 1373-1382.
Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation
Version
AM (Accepted Manuscript)
Published in
American Journal of Respiratory and Critical Care Medicine