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Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation This information is current as of September 29, 2021. Georg Varga, Jan Ehrchen, Anne Brockhausen, Toni Weinhage, Nadine Nippe, Michael Belz, Athanasios Tsianakas, Matthias Ross, Dominik Bettenworth, Tilmann Spieker, Marc Wolf, Ralph Lippe, Klaus Tenbrock, Pieter J. M. Leenen, Johannes Roth and Cord Sunderkötter Downloaded from J Immunol 2014; 193:1090-1099; Prepublished online 2 July 2014; doi: 10.4049/jimmunol.1300891 http://www.jimmunol.org/content/193/3/1090 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2014/07/02/jimmunol.130089 Material 1.DCSupplemental References This article cites 51 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/193/3/1090.full#ref-list-1 by guest on September 29, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation Georg Varga,*,†,‡,1 Jan Ehrchen,*,†,1 Anne Brockhausen,*,† Toni Weinhage,‡ Nadine Nippe,*,† Michael Belz,*,† Athanasios Tsianakas,† Matthias Ross,x Dominik Bettenworth,x Tilmann Spieker,{ Marc Wolf,* Ralph Lippe,* Klaus Tenbrock,‖ Pieter J. M. Leenen,# Johannes Roth,* and Cord Sunderko¨tter*,† Glucocorticoids (GCs) are used as first-line therapies for generalized suppression of inflammation (e.g., allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work revealed that GCs induced a stable anti- inflammatory phenotype in monocytes, the GC-stimulated monocytes (GCsMs) that we exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsMs interact with T cells in suppressing proliferation, as well as cytokine release Downloaded from of CD8+ and, especially, CD4+ T cells in vitro, and that they support generation of Foxp3+ cells. Therefore, we tested their immunosuppressive potential in CD4+ T cell–induced colitis in vivo. We found that injection of GCsMs into mice with severe colitis abolished the inflammation and resulted in significant clinical improvement within a few days. T cells recovered from GCsM-treated mice exhibited reduced secretion of proinflammatory cytokines IFN-g and IL-17. Furthermore, clusters of Foxp3+ CD4+ T cells were detectable at local sites of inflammation in the colon. Thus, GCsMs are able to modify T cell responses in vitro and in vivo, as well as to downregulate and clinically cure severe T cell–mediated colitis. The Journal of Immunology, 2014, 193: 1090–1099. http://www.jimmunol.org/ lucocorticoids (GCs) are the most widely used agents for flammatory cytokines as the result of an interaction between GC suppression of both acute and chronic inflammation, but receptor monomers and proinflammatory transcription factors, such G their wide spectrum of adverse effects limits long-term as NF-kB or AP-1, in a process called “transrepression” (4, 5). GCs treatment. Their clinical efficacy in treating inflammation has also induce anti-inflammatory mediators in monocytes/macrophages been ascribed mainly to their direct inhibitory effects on activated (e.g., annexin A1) (6, 7). immune cells, such as T cells (1) or monocytes/macrophages (2, 3). Moreover, we demonstrated previously that GCs not only down- In monocytes and macrophages they inhibit production of proin- regulate proinflammatory cytokines, they also generate a functionally active, anti-inflammatory phenotype in human monocytes that sup- by guest on September 29, 2021 presses inflammatory processes and, thus, induces resolution of in- *Institute of Immunology, University of Muenster, 48149 Muenster, Germany; flammation (8–10). †Department of Dermatology, University of Muenster, 48149 Muenster, Germany; ‡Pediatric Rheumatology and Immunology, University of Muenster, 48149 Muenster, Monocytes represent a central part of innate immunity. After Germany; xDepartment of Medicine B, University of Muenster, 48149 Muenster, differentiation from stem cells in the bone marrow, monocytes enter Germany; {Institute of Pathology, University of Muenster, 48149 Muenster, Germany; ‖ the circulation and are present in the blood until they migrate into Department of Pediatrics, University of Aachen, Rheinisch Westfa¨lische Technische Hochschule, 52062 Aachen, Germany; and #Department of Immunology, Erasmus tissues where they differentiate into macrophages or dendritic cells Medical Center, 3000 Rotterdam, the Netherlands (DCs). These cells give rise to subtypes that are crucial for nearly 1G.V. and J.E. contributed equally to this work. every step of an immune reaction, including the initiation of an Received for publication April 3, 2013. Accepted for publication May 16, 2014. adaptive immune response, clearance of infectious agents, and res- This work was supported by grants from the Deutsche Forschungsgemeinschaft olution of inflammation (11–16). Subpopulations have been defined (DFG SU 195/3-1 to C.S. and G.V.; DFG SU 195/3-2 to C.S., G.V., and A.B; at the level of circulating monocytes in the human (14) and in the DFG DA 1161/4-1 to T.W.; and DFG EH 397/1-1 to J.E. and C.S.), as well as by murine system (17–19). Reflected by their expression level of IMF VA 22 07 07, IZKF RO 20120, and IZKF Eh2/019/11 (to C.S. and J.E.) (Uni- versity of Muenster). N.N. was supported by SkinStaph Grant FKZ: 01kI07100 from CX3CR1 and CCR2 (as well as Ly6C in mice), monocytes either Bundesministerium fur€ Forschung und Bildung. represent a subtype that selectively migrates into inflamed tissue G.V. and J.E. designed research, performed research, and wrote the manuscript; A.B., M.W., (17, 18, 20) or that forms tissue macrophages and DCs under N.N.,M.B.,A.T.,M.R.,T.S.,R.L.,D.B.,andT.W.performedresearch;K.T.andP.J.M.L. steady-state conditions (reviewed in Refs. 12, 14, 19). designed research; and J.R. and C.S. designed research and wrote the manuscript. In analogy to our studies on human monocytes, we previously The sequences presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE54778) under ac- defined a GC-stimulated murine monocyte subset generated cession number GSE54778. from bone marrow–derived monocytes (21). These murine GC- Address correspondence and reprint requests to Dr. Cord Sunderko¨tter, Department stimulated monocytes (GCsMs) exhibit a stable and distinct phe- of Dermatology, University of Muenster, Von-Esmarch-Straße 58, D-48149 Muen- notype and share with their human counterparts properties such as ster, Germany. E-mail address: [email protected] production of anti-inflammatory mediators and increased migra- The online version of this article contains supplemental material. tory potential (8, 21). In the murine system, GCsMs are charac- Abbreviations used in this article: Ctr-Mo, control monocyte; DC, dendritic cell; GC, low 2 med/high + glucocorticoid; GCsM, glucocorticoid-stimulated monocyte; GITR, glucocorticoid- terized phenotypically as CX3CR1 CCR2 Ly6C CD80 + + induced TNFR-related protein; GO, Gene Ontology; LPMC, lamina propria mono- CD124 CD163 cells (21). This cell surface signature and in- nuclear cell; MDSC, myeloid-derived suppressor cell; MLN, mesenteric lymph node; creased expression of the IL-4Ra-chain (CD124) suggest simi- Treg, regulatory T cell. larity of GCsM to so-called “myeloid-derived suppressor cells” Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 (MDSCs) that were described to suppress T cells and adaptive www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300891 The Journal of Immunology 1091 immune responses (22, 23). Therefore, we hypothesized that analyzed by GCOS Software (Affymetrix), using data from corresponding GCsMs also contribute to regulation of adaptive immune responses, control samples as baseline, and further evaluated statistically, as described especially those mediated by effector T cells. previously (8). They were submitted to the Gene Expression Omnibus under accession number GSE54778. In this study, we approached this hypothesis by genome-wide We retained only genes that were significantly regulated in every ex- expression screening of murine GCsMs and ensuing functional periment (change p value , 0.05; fold change .2, expression over clustering. The data indicated that GC treatment significantly background), as well as in the complete set of experiments (fold-change . , affected the capacity of monocytes to interact with T cells. In agree- 2.0, p value 0.05, paired t test). ment with this, we identified GCsMs as potent suppressors of both Functional clustering CD8+ and CD4+ effector T cell activation in vitro and in vivo.
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  • Foxp2 Loss of Function Increases Striatal Direct Pathway Inhibition Via Increased GABA Release

    Foxp2 Loss of Function Increases Striatal Direct Pathway Inhibition Via Increased GABA Release

    Brain Structure and Function https://doi.org/10.1007/s00429-018-1746-6 ORIGINAL ARTICLE Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release Jon‑Ruben van Rhijn1,2,3 · Simon E. Fisher3,4 · Sonja C. Vernes2,4 · Nael Nadif Kasri1,5 Received: 8 March 2018 / Accepted: 31 August 2018 © The Author(s) 2018 Abstract Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/ inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-medi- ated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive. Keywords Foxp2 · Excitatory-inhibitory balance · Neurodevelopment · D1R-MSN · Striatum Introduction Balanced neuronal activity between cortex, striatum and Sonja C. Vernes and Nael Nadif Kasri contributed equally to this thalamus is essential for the generation of voluntary move- work. ments (Shepherd 2013). Imbalanced activity within the stria- tum is known to disrupt complex motor behaviors, such as Electronic supplementary material The online version of this the production of spoken language (Peach 2004; Square- article (https ://doi.org/10.1007/s0042 9-018-1746-6) contains supplementary material, which is available to authorized users.