Cutting edge: Steroid responsiveness in Foxp31 regulatory T cells determines steroid sensitivity during allergic airway inflammation in mice

Quang Tam Nguyen; Dongkyun Kim; Supinya Iamsawat; Hongnga T. Le; Sohee Kim; Kevin T. Qiu; Terry D. Hinds; Peter Bazeley; John J. O'Shea; Jaehyuk Choi; Kewal Asosingh; Serpil C. Erzurum; Booki Min

doi:10.4049/jimmunol.2100251

Cutting edge: Steroid responsiveness in Foxp31 regulatory T cells determines steroid sensitivity during allergic airway inflammation in mice

Quang Tam Nguyen, Dongkyun Kim, Supinya Iamsawat, Hongnga T. Le, Sohee Kim, Kevin T. Qiu, Terry D. Hinds, Peter Bazeley, John J. O'Shea, Jaehyuk Choi, Kewal Asosingh, Serpil C. Erzurum, Booki Min

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

3 Scopus citations

Abstract

Glucocorticoids are a highly effective first-line treatment option formany inflammatory diseases, including asthma. Some patients develop a steroidresistant condition, yet, the cellular andmolecular mechanisms underlying steroid resistance remain largely unknown. In this study, we used a murine model of steroid-resistant airway inflammation and report that combining systemic dexamethasone and intranasal IL-27 is able to reverse the inflammation. Foxp3+ regulatory T cells (Tregs) were required during dexamethasone/IL-27 treatment of steroid-resistant allergic inflammation, and importantly, direct stimulation of Tregs via glucocorticoid or IL-27 receptors was essential. Mechanistically, IL-27 stimulation in Tregs enhanced expression of the agonistic glucocorticoid receptor-a isoform. Overexpression of inhibitory glucocorticoid receptor-β isoform in Tregs alone was sufficient to elicit steroid resistance in a steroid- sensitive allergic inflammation model. Taken together, our results demonstrate for the first time, to our knowledge, that Tregs are instrumental during steroid resistance and that manipulating steroid responsiveness in Tregs may represent a novel strategy to treat steroid refractory asthma.

Original language	English
Pages (from-to)	765-770
Number of pages	6
Journal	Journal of Immunology
Volume	207
Issue number	3
DOIs	https://doi.org/10.4049/jimmunol.2100251
State	Published - Aug 1 2021

Bibliographical note

Funding Information:
This work was supported by National Institute of Allergy and Infectious Diseases, National Institutes of Health grants AI125247 and AI147498 (to B.M.), by American Asthma Foundation Scholar Award (to B.M.), and by National Heart, Lung, and Blood Institute, National Institutes of Health Grants HL103453, HL081064, HL60917, and HL109250 (to K.A. and S.C.E).

Funding Information:
This work was supported by National Institute of Allergy and Infectious Diseases, National Institutes of Health grants AI125247 and AI147498 (to B.M.), by American Asthma

Funding Information:
Foundation Scholar Award (to B.M.), and by National Heart, Lung, and Blood Institute, National Institutes of Health Grants HL103453, HL081064, HL60917, and HL109250 (to K.A. and S.C.E).

Publisher Copyright:
Copyright © 2021 by The American Association of Immunologists, Inc. All rights reserved.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.4049/jimmunol.2100251

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Nguyen, Q. T., Kim, D., Iamsawat, S., Le, H. T., Kim, S., Qiu, K. T., Hinds, T. D., Bazeley, P., O'Shea, J. J., Choi, J., Asosingh, K., Erzurum, S. C., & Min, B. (2021). Cutting edge: Steroid responsiveness in Foxp31 regulatory T cells determines steroid sensitivity during allergic airway inflammation in mice. Journal of Immunology, 207(3), 765-770. https://doi.org/10.4049/jimmunol.2100251

@article{1cfbdd2e310a4e048d7d34e05d4f1207,

title = "Cutting edge: Steroid responsiveness in Foxp31 regulatory T cells determines steroid sensitivity during allergic airway inflammation in mice",

abstract = "Glucocorticoids are a highly effective first-line treatment option formany inflammatory diseases, including asthma. Some patients develop a steroidresistant condition, yet, the cellular andmolecular mechanisms underlying steroid resistance remain largely unknown. In this study, we used a murine model of steroid-resistant airway inflammation and report that combining systemic dexamethasone and intranasal IL-27 is able to reverse the inflammation. Foxp3+ regulatory T cells (Tregs) were required during dexamethasone/IL-27 treatment of steroid-resistant allergic inflammation, and importantly, direct stimulation of Tregs via glucocorticoid or IL-27 receptors was essential. Mechanistically, IL-27 stimulation in Tregs enhanced expression of the agonistic glucocorticoid receptor-a isoform. Overexpression of inhibitory glucocorticoid receptor-β isoform in Tregs alone was sufficient to elicit steroid resistance in a steroid- sensitive allergic inflammation model. Taken together, our results demonstrate for the first time, to our knowledge, that Tregs are instrumental during steroid resistance and that manipulating steroid responsiveness in Tregs may represent a novel strategy to treat steroid refractory asthma.",

author = "Nguyen, {Quang Tam} and Dongkyun Kim and Supinya Iamsawat and Le, {Hongnga T.} and Sohee Kim and Qiu, {Kevin T.} and Hinds, {Terry D.} and Peter Bazeley and O'Shea, {John J.} and Jaehyuk Choi and Kewal Asosingh and Erzurum, {Serpil C.} and Booki Min",

note = "Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases, National Institutes of Health grants AI125247 and AI147498 (to B.M.), by American Asthma Foundation Scholar Award (to B.M.), and by National Heart, Lung, and Blood Institute, National Institutes of Health Grants HL103453, HL081064, HL60917, and HL109250 (to K.A. and S.C.E). Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases, National Institutes of Health grants AI125247 and AI147498 (to B.M.), by American Asthma Funding Information: Foundation Scholar Award (to B.M.), and by National Heart, Lung, and Blood Institute, National Institutes of Health Grants HL103453, HL081064, HL60917, and HL109250 (to K.A. and S.C.E). Publisher Copyright: Copyright {\textcopyright} 2021 by The American Association of Immunologists, Inc. All rights reserved.",

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Nguyen, QT, Kim, D, Iamsawat, S, Le, HT, Kim, S, Qiu, KT, Hinds, TD, Bazeley, P, O'Shea, JJ, Choi, J, Asosingh, K, Erzurum, SC & Min, B 2021, 'Cutting edge: Steroid responsiveness in Foxp31 regulatory T cells determines steroid sensitivity during allergic airway inflammation in mice', Journal of Immunology, vol. 207, no. 3, pp. 765-770. https://doi.org/10.4049/jimmunol.2100251

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AU - Nguyen, Quang Tam

AU - Kim, Dongkyun

AU - Iamsawat, Supinya

AU - Le, Hongnga T.

AU - Kim, Sohee

AU - Qiu, Kevin T.

AU - Hinds, Terry D.

AU - Bazeley, Peter

AU - O'Shea, John J.

AU - Choi, Jaehyuk

AU - Asosingh, Kewal

AU - Erzurum, Serpil C.

AU - Min, Booki

N1 - Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases, National Institutes of Health grants AI125247 and AI147498 (to B.M.), by American Asthma Foundation Scholar Award (to B.M.), and by National Heart, Lung, and Blood Institute, National Institutes of Health Grants HL103453, HL081064, HL60917, and HL109250 (to K.A. and S.C.E). Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases, National Institutes of Health grants AI125247 and AI147498 (to B.M.), by American Asthma Funding Information: Foundation Scholar Award (to B.M.), and by National Heart, Lung, and Blood Institute, National Institutes of Health Grants HL103453, HL081064, HL60917, and HL109250 (to K.A. and S.C.E). Publisher Copyright: Copyright © 2021 by The American Association of Immunologists, Inc. All rights reserved.

PY - 2021/8/1

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N2 - Glucocorticoids are a highly effective first-line treatment option formany inflammatory diseases, including asthma. Some patients develop a steroidresistant condition, yet, the cellular andmolecular mechanisms underlying steroid resistance remain largely unknown. In this study, we used a murine model of steroid-resistant airway inflammation and report that combining systemic dexamethasone and intranasal IL-27 is able to reverse the inflammation. Foxp3+ regulatory T cells (Tregs) were required during dexamethasone/IL-27 treatment of steroid-resistant allergic inflammation, and importantly, direct stimulation of Tregs via glucocorticoid or IL-27 receptors was essential. Mechanistically, IL-27 stimulation in Tregs enhanced expression of the agonistic glucocorticoid receptor-a isoform. Overexpression of inhibitory glucocorticoid receptor-β isoform in Tregs alone was sufficient to elicit steroid resistance in a steroid- sensitive allergic inflammation model. Taken together, our results demonstrate for the first time, to our knowledge, that Tregs are instrumental during steroid resistance and that manipulating steroid responsiveness in Tregs may represent a novel strategy to treat steroid refractory asthma.

AB - Glucocorticoids are a highly effective first-line treatment option formany inflammatory diseases, including asthma. Some patients develop a steroidresistant condition, yet, the cellular andmolecular mechanisms underlying steroid resistance remain largely unknown. In this study, we used a murine model of steroid-resistant airway inflammation and report that combining systemic dexamethasone and intranasal IL-27 is able to reverse the inflammation. Foxp3+ regulatory T cells (Tregs) were required during dexamethasone/IL-27 treatment of steroid-resistant allergic inflammation, and importantly, direct stimulation of Tregs via glucocorticoid or IL-27 receptors was essential. Mechanistically, IL-27 stimulation in Tregs enhanced expression of the agonistic glucocorticoid receptor-a isoform. Overexpression of inhibitory glucocorticoid receptor-β isoform in Tregs alone was sufficient to elicit steroid resistance in a steroid- sensitive allergic inflammation model. Taken together, our results demonstrate for the first time, to our knowledge, that Tregs are instrumental during steroid resistance and that manipulating steroid responsiveness in Tregs may represent a novel strategy to treat steroid refractory asthma.

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Cutting edge: Steroid responsiveness in Foxp31 regulatory T cells determines steroid sensitivity during allergic airway inflammation in mice

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