TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma

David F Choy; Kevin M Hart; Lee A Borthwick; Aarti Shikotra; Deepti R Nagarkar; Salman Siddiqui; Guiquan Jia; Chandra M Ohri; Emma Doran; Kevin M Vannella; Claire Butler; Beverley Hargadon; Joshua C Sciurba; Richard L Gieseck; Robert W Thompson; Sandra White; Alexander R Abbas; Janet Jackman; Lawren C Wu; Jackson G Egen; Liam G Heaney; Thirumalai R Ramalingam; Joseph R Arron; Thomas A Wynn; Peter Bradding

doi:10.1126/scitranslmed.aab3142

TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma

David F Choy, Kevin M Hart, Lee A Borthwick, Aarti Shikotra, Deepti R Nagarkar, Salman Siddiqui, Guiquan Jia, Chandra M Ohri, Emma Doran, Kevin M Vannella, Claire Butler, Beverley Hargadon, Joshua C Sciurba, Richard L Gieseck, Robert W Thompson, Sandra White, Alexander R Abbas, Janet Jackman, Lawren C Wu, Jackson G EgenLiam G Heaney, Thirumalai R Ramalingam, Joseph R Arron, Thomas A Wynn, Peter Bradding

Research output: Contribution to journal › Article › peer-review

402 Citations (Scopus)

Abstract

Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. 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 TH2/17-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 interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (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-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and 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.

Original language	English
Article number	301ra129
Journal	Science Translational Medicine
Volume	7
Issue number	301
DOIs	https://doi.org/10.1126/scitranslmed.aab3142
Publication status	Published - 19 Aug 2015

Keywords

Asthma
Heterogeneity

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Liam Heaney
- l.heaneyqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Clinical Professor
- Wellcome Wolfson Institute for Experimental Medicine
Person: Academic

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Choy, D. F., Hart, K. M., Borthwick, L. A., Shikotra, A., Nagarkar, D. R., Siddiqui, S., Jia, G., Ohri, C. M., Doran, E., Vannella, K. M., Butler, C., Hargadon, B., Sciurba, J. C., Gieseck, R. L., Thompson, R. W., White, S., Abbas, A. R., Jackman, J., Wu, L. C., ... Bradding, P. (2015). TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Science Translational Medicine, 7(301), Article 301ra129. https://doi.org/10.1126/scitranslmed.aab3142

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title = "TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma",

abstract = "Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. 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 TH2/17-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 interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (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-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and 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.",

keywords = "Asthma, Heterogeneity",

author = "Choy, {David F} and Hart, {Kevin M} and Borthwick, {Lee A} and Aarti Shikotra and Nagarkar, {Deepti R} and Salman Siddiqui and Guiquan Jia and Ohri, {Chandra M} and Emma Doran and Vannella, {Kevin M} and Claire Butler and Beverley Hargadon and Sciurba, {Joshua C} and Gieseck, {Richard L} and Thompson, {Robert W} and Sandra White and Abbas, {Alexander R} and Janet Jackman and Wu, {Lawren C} and Egen, {Jackson G} and Heaney, {Liam G} and Ramalingam, {Thirumalai R} and Arron, {Joseph R} and Wynn, {Thomas A} and Peter Bradding",

year = "2015",

month = aug,

day = "19",

doi = "10.1126/scitranslmed.aab3142",

language = "English",

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journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

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Choy, DF, Hart, KM, Borthwick, LA, Shikotra, A, Nagarkar, DR, Siddiqui, S, Jia, G, Ohri, CM, Doran, E, Vannella, KM, Butler, C, Hargadon, B, Sciurba, JC, Gieseck, RL, Thompson, RW, White, S, Abbas, AR, Jackman, J, Wu, LC, Egen, JG, Heaney, LG, Ramalingam, TR, Arron, JR, Wynn, TA & Bradding, P 2015, 'TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma', Science Translational Medicine, vol. 7, no. 301, 301ra129. https://doi.org/10.1126/scitranslmed.aab3142

TY - JOUR

T1 - TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma

AU - Choy, David F

AU - Hart, Kevin M

AU - Borthwick, Lee A

AU - Shikotra, Aarti

AU - Nagarkar, Deepti R

AU - Siddiqui, Salman

AU - Jia, Guiquan

AU - Ohri, Chandra M

AU - Doran, Emma

AU - Vannella, Kevin M

AU - Butler, Claire

AU - Hargadon, Beverley

AU - Sciurba, Joshua C

AU - Gieseck, Richard L

AU - Thompson, Robert W

AU - White, Sandra

AU - Abbas, Alexander R

AU - Jackman, Janet

AU - Wu, Lawren C

AU - Egen, Jackson G

AU - Heaney, Liam G

AU - Ramalingam, Thirumalai R

AU - Arron, Joseph R

AU - Wynn, Thomas A

AU - Bradding, Peter

PY - 2015/8/19

Y1 - 2015/8/19

N2 - Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. 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 TH2/17-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 interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (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-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and 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.

AB - Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. 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 TH2/17-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 interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (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-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and 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.

KW - Asthma

KW - Heterogeneity

U2 - 10.1126/scitranslmed.aab3142

DO - 10.1126/scitranslmed.aab3142

M3 - Article

C2 - 26290411

SN - 1946-6234

VL - 7

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 301

M1 - 301ra129

ER -

TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma

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