Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3+ Regulatory T Cells via a miR-342-Dependent Mechanism

Dongkyun Kim; Quang Tam Nguyen; Juyeun Lee; Sung Hwan Lee; Allison Janocha; Sohee Kim; Hongnga T. Le; Nina Dvorina; Kelly Weiss; Mark J. Cameron; Kewal Asosingh; Serpil C. Erzurum; William M. Baldwin; Ju Seog Lee; Booki Min

doi:10.1016/j.immuni.2020.07.002

Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3⁺ Regulatory T Cells via a miR-342-Dependent Mechanism

Dongkyun Kim, Quang Tam Nguyen, Juyeun Lee, Sung Hwan Lee, Allison Janocha, Sohee Kim, Hongnga T. Le, Nina Dvorina, Kelly Weiss, Mark J. Cameron, Kewal Asosingh, Serpil C. Erzurum, William M. Baldwin, Ju Seog Lee, Booki Min^*

^*Corresponding author for this work

Microbiology-Immunology

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

75 Scopus citations

Abstract

Glucocorticoids (GC) are the mainstay treatment option for inflammatory conditions. Despite the broad usage of GC, the mechanisms by which GC exerts its effects remain elusive. Here, utilizing murine autoimmune and allergic inflammation models, we report that Foxp3⁺ regulatory T (Treg) cells are irreplaceable GC target cells in vivo. Dexamethasone (Dex) administered in the absence of Treg cells completely lost its ability to control inflammation, and the lack of glucocorticoid receptor in Treg cells alone resulted in the loss of therapeutic ability of Dex. Mechanistically, Dex induced miR-342-3p specifically in Treg cells and miR-342-3p directly targeted the mTORC2 component, Rictor. Altering miRNA-342-3p or Rictor expression in Treg cells dysregulated metabolic programming in Treg cells, controlling their regulatory functions in vivo. Our results uncover a previously unknown contribution of Treg cells during glucocorticoid-mediated treatment of inflammation and the underlying mechanisms operated via the Dex-miR-342-Rictor axis.

Original language	English (US)
Pages (from-to)	581-596.e5
Journal	Immunity
Volume	53
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2020.07.002
State	Published - Sep 15 2020

Funding

The authors thank Ms. Jennifer Powers for cell sorting and Brian Richardson for RNA-seq data preparation. This work was supported by the National Institutes of Health grants R01-AI125247 and R01-AI147498 (B.M.) and by the National Multiple Sclerosis Society Research Grants RG1411-02051 and RG1806-31374 (B.M.). This work was also supported in part by Cancer Prevention & Research Institute of Texas grant RP170307 (J-S.L.), by Congressionally Directed Medical Research Program grant CA160616 (J-S.L.), and by National Institutes of Health grants HL103453 , HL081064 , HL60917 , and HL109250 (K.A. and S.C.E).

Keywords

Treg cells
allergic inflammation
autoimmune inflammation
glucocorticoids
metabolism
miRNA

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.immuni.2020.07.002

Cite this

Kim, D., Nguyen, Q. T., Lee, J., Lee, S. H., Janocha, A., Kim, S., Le, H. T., Dvorina, N., Weiss, K., Cameron, M. J., Asosingh, K., Erzurum, S. C., Baldwin, W. M., Lee, J. S., & Min, B. (2020). Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3⁺ Regulatory T Cells via a miR-342-Dependent Mechanism. Immunity, 53(3), 581-596.e5. https://doi.org/10.1016/j.immuni.2020.07.002

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title = "Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3+ Regulatory T Cells via a miR-342-Dependent Mechanism",

abstract = "Glucocorticoids (GC) are the mainstay treatment option for inflammatory conditions. Despite the broad usage of GC, the mechanisms by which GC exerts its effects remain elusive. Here, utilizing murine autoimmune and allergic inflammation models, we report that Foxp3+ regulatory T (Treg) cells are irreplaceable GC target cells in vivo. Dexamethasone (Dex) administered in the absence of Treg cells completely lost its ability to control inflammation, and the lack of glucocorticoid receptor in Treg cells alone resulted in the loss of therapeutic ability of Dex. Mechanistically, Dex induced miR-342-3p specifically in Treg cells and miR-342-3p directly targeted the mTORC2 component, Rictor. Altering miRNA-342-3p or Rictor expression in Treg cells dysregulated metabolic programming in Treg cells, controlling their regulatory functions in vivo. Our results uncover a previously unknown contribution of Treg cells during glucocorticoid-mediated treatment of inflammation and the underlying mechanisms operated via the Dex-miR-342-Rictor axis.",

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author = "Dongkyun Kim and Nguyen, {Quang Tam} and Juyeun Lee and Lee, {Sung Hwan} and Allison Janocha and Sohee Kim and Le, {Hongnga T.} and Nina Dvorina and Kelly Weiss and Cameron, {Mark J.} and Kewal Asosingh and Erzurum, {Serpil C.} and Baldwin, {William M.} and Lee, {Ju Seog} and Booki Min",

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Kim, D, Nguyen, QT, Lee, J, Lee, SH, Janocha, A, Kim, S, Le, HT, Dvorina, N, Weiss, K, Cameron, MJ, Asosingh, K, Erzurum, SC, Baldwin, WM, Lee, JS & Min, B 2020, 'Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3⁺ Regulatory T Cells via a miR-342-Dependent Mechanism', Immunity, vol. 53, no. 3, pp. 581-596.e5. https://doi.org/10.1016/j.immuni.2020.07.002

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AU - Kim, Dongkyun

AU - Nguyen, Quang Tam

AU - Lee, Juyeun

AU - Lee, Sung Hwan

AU - Janocha, Allison

AU - Kim, Sohee

AU - Le, Hongnga T.

AU - Dvorina, Nina

AU - Weiss, Kelly

AU - Cameron, Mark J.

AU - Asosingh, Kewal

AU - Erzurum, Serpil C.

AU - Baldwin, William M.

AU - Lee, Ju Seog

AU - Min, Booki

PY - 2020/9/15

Y1 - 2020/9/15

N2 - Glucocorticoids (GC) are the mainstay treatment option for inflammatory conditions. Despite the broad usage of GC, the mechanisms by which GC exerts its effects remain elusive. Here, utilizing murine autoimmune and allergic inflammation models, we report that Foxp3+ regulatory T (Treg) cells are irreplaceable GC target cells in vivo. Dexamethasone (Dex) administered in the absence of Treg cells completely lost its ability to control inflammation, and the lack of glucocorticoid receptor in Treg cells alone resulted in the loss of therapeutic ability of Dex. Mechanistically, Dex induced miR-342-3p specifically in Treg cells and miR-342-3p directly targeted the mTORC2 component, Rictor. Altering miRNA-342-3p or Rictor expression in Treg cells dysregulated metabolic programming in Treg cells, controlling their regulatory functions in vivo. Our results uncover a previously unknown contribution of Treg cells during glucocorticoid-mediated treatment of inflammation and the underlying mechanisms operated via the Dex-miR-342-Rictor axis.

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