Buttgereit, Frank

Gaber, Timo

English

Institutional Repository of the Freie Universität Berlin

RESEARCH HIGHLIGHT OPENNew insights into the fascinating world of glucocorticoids: thedexamethasone-miR-342-Rictor axis in regulatory T cellsFrank Buttgereit 1 and Timo Gaber 1Cellular & Molecular Immunology (2021) 18:520–522; https://doi.org/10.1038/s41423-020-00598-0In a recent issue of Immunity, Kim et al. reported previouslyunknown effects of glucocorticoids on murine regulatory T (Treg)cells, and this report added another very interesting perspective tothe already very diverse body of knowledge about theseimportant hormones and therapeutics compared to the body ofknowledge about other clinically used drugs.1 Treg cells areimportant regulators of the immune response in autoimmune andallergic inflammation. Both human and murine Treg cells arecharacterized by high expression of the cytokine IL-2 receptor αchain (CD25) and expression of the transcription factor Foxp3,which is necessary for the development, function and stability ofthese cells. The main function of Treg cells is the regulation orsuppression other immune cell functions, such as the activation,proliferation, and cytokine production of CD4+ T cells, CD8+T cells, B cells, and dendritic cells. In this way, Treg cells control theimmune response to antigens, including toxins, chemicals,bacteria, viruses, or other substances, that come from outsidethe body as well as the immune response to self-antigens, therebyhelping to prevent autoimmune disease. However, little is knownabout the effects of glucocorticoids on these cells. This lack ofunderstanding is initially surprising because Treg cells wereidentified many years ago, and research in the field ofglucocorticoids is very intensive due to the immense clinicalimportance of these therapeutics. Given this background, the newinsights gained represent an important enrichment of ourknowledge about both Treg cells and the mechanisms ofglucocorticoid action and may help to identify new ways tooptimize the benefit-risk ratio of these important drugs.For more than 70 years, glucocorticoids have represented anintegral part of modern clinical medicine.2 In rheumatology alone,glucocorticoids are mentioned in many current recommendations,e.g., for the management of rheumatoid arthritis, large vesselvasculitides, polymyalgia rheumatica and giant cell arteritis. Insharp contrast to this very high clinical significance, the exactmechanisms of action are understood in less detail.3 However, weare constantly learning more. Only recently, very interestingfindings about the contribution of prereceptor glucocorticoidmetabolism by the hydroxysteroid dehydrogenase enzyme 11β-HSD1 to anti-inflammatory mechanisms were published. Fentonet al. reported that glucocorticoid molecules that have undergonesystemic inactivation are peripherally (i.e., locally in the inflamma-tion area) reactivated by the enzyme 11β-HSD1 to exert stronganti-inflammatory effects. The nicotinamide adenine dinucleotidephosphate (NADPH)-dependent enzyme 11β-HSD1 is upregulatedin inflammatory regions and causes local glucocorticoidactivation.4 This phenomenon facilitates binding to cytosolicglucocorticoid receptor α to trigger genomic effects (Fig. 1).In addition to these unique properties of prereceptor metabo-lism, the second level of complexity of the effects of glucocorti-coids arises from the variety of genomic and nongenomic effectsinduced by glucocorticoids (Fig. 1).2 Due to the lack of space, thecurrent state of knowledge cannot be discussed here, but anupdated tabular summary can be found in Buttgereit.3Third, the great variety and complexity of the effects ofglucocorticoid are determined by the fact that these effects arehighly dependent on cell type (Fig. 1). In a recent study, Francoet al. aimed to develop a greater understanding of howglucocorticoids affect distinct cell subsets.5 To this end, theseauthors studied the genome-wide transcriptional response toglucocorticoids in nine primary human hematopoietic andnonhematopoietic cell types, namely, B cells, CD4+ T cells,monocytes, neutrophils, endothelial cells, osteoblasts, myoblasts,fibroblasts, and preadipocytes, all of which were obtained fromhealthy donors. As a key result, the authors revealed a strong andpreviously undescribed cell type-specific transcriptional responseto glucocorticoids. In detail, the authors found that theglucocorticoid methylprednisolone induces cell-specific differ-ences in the regulation of genes and signaling pathways. Thesedifferences affected more than 9000 unique genes, whichcorresponds to ~17% of the human transcriptome. Cell-specificobservations such as this have the potential to facilitate thedevelopment of more selective immunoregulatory therapies.In this context, the work of Kim et al. now makes a decisivecontribution.1 The authors started by demonstrating Foxp3+ Tregcells to be necessary for the glucocorticoid-induced inhibition ofinflammatory reactions. The data revealed, in mouse models ofexperimental autoimmune encephalomyelitis and allergic airwayinflammation, that dexamethasone was no longer able to inhibitinflammation in the absence of Treg cells. In a series of elegantfollow-up experiments, the authors first showed that dexametha-sone administered at the beginning of the disease effectivelyattenuated the signs of inflammation or clinical symptoms.However, when Treg cells were depleted, dexamethasone wasno longer able to exert these effects. In turn, the transfer of Tregcells was shown to restore the therapeutic effect of dexametha-sone treatment. Consistent observations were made in Treg cell-specific glucocorticoid receptor-deficient mice. In these animals,the lack of endogenous glucocorticoid signaling in Treg cells hadlittle impact on immune homeostasis under steady state condi-tions, and the course of experimental autoimmune encephalo-myelitis remained unchanged despite treatment withReceived: 6 November 2020 Accepted: 11 November 2020Published online: 6 January 20211Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, GermanyCorrespondence: Frank Buttgereit (frank.buttgereit@charite.de)www.nature.com/cmi Cellular & Molecular Immunology© The Author(s) 20201234567890();,:dexamethasone. What is the underlying mechanism that explainsthese interesting and clinically very relevant observations? Theauthors reported that dexamethasone triggered a signal specifi-cally in Treg cells that mediated the therapeutic effects. In thiscontext, the authors coined a new term, namely, the identificationof the ‘dexamethasone-miR-342-Rictor axis’. In detail, the authorsdemonstrated that dexamethasone induces miRNA-342-3p in Tregcells. MicroRNA-342 (miR-342) is a highly conserved microRNAencoded by the third intron of the Evl gene. This gene is one ofthe genes induced by dexamethasone in Treg cells and encodesthe Ena-vasodilator stimulated phosphoprotein, an actin-associated protein involved in various processes associated withcytoskeleton remodeling and cell polarity.1 The general functionof microRNAs, which are small noncoding RNA molecules, is themodification of both the stability and translation of mRNAs, whichultimately leads to RNA silencing and posttranscriptional regula-tion of gene expression. Specifically, for Treg cells, the authorsreported that Rictor, an mTOR complex 2 molecule, served as apotential target of miR-342-3p. Indeed, the modulation of miR-342and Rictor expression could influence the metabolic profile andthus the suppressive function of Treg cells. It was concluded thatdexamethasone induced the miR-342-3p-mediated downregula-tion of Rictor in Treg cells, which preserved oxidative phosphor-ylation (OXPHOS) metabolic programming and limited theglycolytic pathway, thereby mediating anti-inflammatory effects.Examining the metabolism of Treg cells in detail certainly wouldhave been slightly beyond the scope of this paper. Therefore, theauthors end the article with the conclusion that thedexamethasone-mediated downregulation of Rictor via miR-342-3p enhanced the suppressive functions of Treg cells by supportingOXPHOS and inhibiting the enhancement of glycolytic pathways.Nevertheless, there is much to be said on this subject because, inrecent years, a new field called immunometabolism has emerged,which focuses on changes in intracellular metabolic pathways inimmune cells that alter their function.6 We and others haverecently described the complex interplay between metabolicreprogramming and immunity.6,7The reprogramming of metabolism from OXPHOS to aerobicglycolysis (the ‘Warburg effect’) upon cell activation is a hallmarkof effector T cells. Conversely, FOXP3+ Treg cells do not requirehigh rates of glycolysis and high uptake of glucose or glutaminebut mainly depend on the oxidation of mitochondrial lipids,pyruvate, and lactate.7 Moreover, the Treg transcription factorFoxp3 itself intervenes with Treg metabolism by downregulatingglycolysis, inducing OXPHOS, and increasing the NAD:NADH ratio.Under metabolically challenging conditions, lactate impairseffector T cells through lactate dehydrogenase (LDH)-mediatedNAD depletion, which can be replenished in Tregs by OXPHOS.These metabolic adaptations enable Tregs to maintain theirimmunosuppressive function in low-glucose, lactate-rich environ-ments.7 In contrast, high rates of glucose metabolism can impairthe suppressive capacity of Treg cells by inducing mTORC1, whilelower levels of mTORC1 activity are still necessary for proper Tregfunction. In the absence of any mTORC1 function, Treg cells fail tosuppress effector T cells. Conversely, the mTORC1 inhibitorrapamycin is capable of promoting the development of Tregs.7When Tregs fail to properly differentiate and thus becomedysfunctional, as observed in patients suffering from immuno-dysregulation polyendocrinopathy enteropathy X-linked (IPEX)syndrome, enhanced phosphorylation of mTORC2, but notmTORC1, can be observed. Conversely, treatment of Tregsobtained from these patients with an mTOR inhibitor restorestheir suppressive function.8 In Foxp3-deficient murine Treg cells,the regulatory function can be re-established by specificallydeleting the mTORC2 adapter gene Rictor but not by deleting themTORC1 adaptor gene Rptor.8 Moreover, deletion of Foxo1, theexpression of which is reduced due to hyperactivation in Foxp3-mutated Tregs, impairs the reversal of IPEX syndrome in mTORC2KO mice. Thus, inhibition of Foxo1 by mTORC2 reduces thesuppressive capacity of Tregs by enhancing their glycolytic rate.8Given this background, the interesting findings provided by Kimet al. complete our understanding of the reprogramming ofimmunometabolism from glycolysis back to OXPHOS to enhanceimmune suppression by targeting mTORC2 (including Rictor).1In summary, the publication by Kim et al. describes carefullyconducted experiments with clear and novel conclusions, but italso has limitations. First, it needs to be shown that the findingsobtained in murine models can also be confirmed in human Tregcells. Second, the authors argue that the continuation of thisresearch could lead to the identification of new therapeutictargets, for example, to better control glucocorticoid-resistantinflammation by targeting the miR-342-Rictor axis in Treg cells.However, no precise and comprehensible concept of how thisidea should be implemented in the near future is discernible. Ofnote, the latter would be urgently needed to further anddecisively improve the current benefit-risk ratio of treatmentsincluding glucocorticoids.9,10FUNDINGOpen Access funding enabled and organized by Projekt DEAL.11β11β-HSD1inactive GC active GC-HSD2inactive GC active GC-HSD1 Enzyme upregulationduring inflammationAGenomic and non-genomicmechanisms of actionCell-specific effectsother(immune) cells monocytes CD4+ T cellsTregcellsmiRNA-342-3p Rictormetabolic effectsfunctional effectsgranulocytesImmune cellsBC11βFig. 1 Determinants of the therapeutic effects of glucocorticoids.A At the systemic level, shuttling between active and inactive formsof circulating glucocorticoids (GC) is mediated by the actions of11β-HSD (hydroxysteroid dehydrogenase) enzymes. B The periph-eral upregulation of 11β-HSD1 in inflamed regions locally reactivatesinactive glucocorticoid molecules. C Both systemic and localprereceptor metabolism determines the strength of genomic andnongenomic effects in a cell-specific manner. In Foxp3+ regulatoryT cells, the anti-inflammatory roles of glucocorticoids are mediatedvia a miR-342-dependent mechanism.1 Medical images adaptedfrom Servier Medical Art, http://smart.servier.com/, licensed under aCreative Commons Attribution 3.0 Unported LicenseNew insights into the fascinating world of glucocorticoids: the. . .F Buttgereit and T Gaber521Cellular & Molecular Immunology (2021) 18:520 – 522ADDITIONAL INFORMATIONCompeting interests: The authors declare no competing interests.REFERENCES1. Kim, D. et al. Immunity 53, 581–596 e585 (2020).2. Strehl, C., Ehlers, L., Gaber, T. & Buttgereit, F. Front Immunol. 10, 1744 (2019).3. Buttgereit, F. Ann. Rheum. Dis. 2020:annrheumdis-2020-218798.4. Fenton C., et al. Ann. Rheum. Dis. 2020:annrheumdis-2020-218493.5. Franco, L. M. et al. J. Exp. Med. 216, 384–406 (2019).6. O’Neill, L. A., Kishton, R. J. & Rathmell, J. Nat. Rev. Immunol. 16, 553–565 (2016).7. Gaber, T., Chen, Y., Krauss, P. L. & Buttgereit, F. Int Rev. Cell Mol. Biol. 342, 95–148 (2019).8. Charbonnier, L. M. et al. Nat. Immunol. 20, 1208–1219 (2019).9. Buttgereit, F., Bijlsma, J. W. J. & Strehl, C. Clin. Immunol. 186, 64–66 (2018).10. van der Goes, M. C., Strehl, C., Buttgereit, F., Bijlsma, J. W. & Jacobs, J. W. ExpertOpin. Pharmacother. 17, 2129–2133 (2016).Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in anymedium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2020New insights into the fascinating world of glucocorticoids: the. . .F Buttgereit and T Gaber522Cellular & Molecular Immunology (2021) 18:520 – 522

New insights into the fascinating world of glucocorticoids: the dexamethasone-miR-342-Rictor axis in regulatory T cells

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New insights into the fascinating world of glucocorticoids: the dexamethasone-miR-342-Rictor axis in regulatory T cells

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