TY - JOUR
T1 - Cutting edge
T2 - Steroid responsiveness in Foxp31 regulatory T cells determines steroid sensitivity during allergic airway inflammation in mice
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 - Publisher Copyright:
Copyright © 2021 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2021/8/1
Y1 - 2021/8/1
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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U2 - 10.4049/jimmunol.2100251
DO - 10.4049/jimmunol.2100251
M3 - Article
C2 - 34301840
AN - SCOPUS:85112490350
SN - 0022-1767
VL - 207
SP - 765
EP - 770
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -