Th2 and Th17 inflammatory pathways are reciprocally regulated in asthma
journal contributionposted on 2015-08-21, 10:42 authored by D. F. Choy, K. M. Hart, L. A. Borthwick, Aarti Shikotra, D. R. Nagarkar, Salman Siddiqui, G. Jia, Chandra M. Ohri, E. Doran, K. M. Vannella, C. A. Butler, Beverley Hargadon, J. C. Sciurba, R. L. Gieseck, R. W. Thompson, S. White, A. R. Abbas, J. Jackman, L. C. Wu, J. G. Egen, L. G. Heaney, T. R. Ramalingam, J. R. Arron, T. A. Wynn, Peter Bradding
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. Here, in a cross-sectional study of asthmatics of varying severity (n=51), endobronchial tissue gene expression analysis revealed three major patient clusters: Th2-high, Th17-high, and Th2/Th17-low. Th2-high and Th17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by IL-13 and IL-17A. To understand this dichotomous pattern of Th2 and Th17 signatures, we investigated the potential of type 2 cytokine suppression in promoting Th17 responses in a preclinical model of allergen induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased Th17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-1 and IL-17 protected subjects from eosinophilia, mucus hyperplasia, airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both Th2 and Th17 endotypes.
Supported in part by the Intramural Research Program of the NIH, NIAID. Work in Leicester was supported by grants from Asthma UK project grant AUK-PG- 2013-208 and a grant-in-aid from Genentech,Inc., and was supported by the National Institute for Health Research Leicester Respiratory Biomedical Research Unit.
CitationScience Translational Medicine 19 Aug 2015: Vol. 7, Issue 301, pp. 301ra129
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation
- AM (Accepted Manuscript)