Abstract
For the maintenance of homeostasis termination of immune reactions is as equally important as their induction. In this scenario regulatory T cells (Treg) play an important role. Accordingly a variety of inflammatory diseases are caused by an impairment of Treg. Hence, it is important to identify triggers by which Treg can be induced and activated, respectively. For quite a long time it is known that ultraviolet radiation can induce Treg which inhibit cutaneous immune reactions including contact hypersensitivity. Since these Treg inhibit in an antigen-specific fashion they may harbor therapeutic potential. However similar Treg can be induced also by other triggers which include vitamin D and antimicrobial peptides. Recently it was discovered that the gut microbiome controls the development of Treg in the intestine. The same may apply for the skin. Short chain fatty acids, microbiota-derived bacterial fermentation products, appear to induce and to activate Treg in the skin. Topical application of short chain fatty acids was shown to inhibit contact hypersensitivity and to reduce inflammation in the murine imiquimod-induced psoriasis-like skin inflammation model. Together, these data indicate that induction and activation of Treg may be a potential therapeutic strategy to treat inflammatory diseases in the future.
Funding source: German Research Foundation
Funding source: Interdisciplinary Center of Clinical Research of the Medical Faculty of the Westfalian-Wilhelms-University Münster
Funding source: Federal Ministry of Education and Research
Funding source: Federal Ministry of Environmental Protection
Funding source: European Community
Funding source: CERIES Award (Chanel)
Funding source: Exposome Grant (Vichy)
About the authors
Thomas Schwarz received his MD at the University of Vienna, Austria. He is currently full professor and director of the Department of Dermatology at the University Clinics, Schleswig-Holstein, Campus Kiel. His work focuses on the effect of ultraviolet radiation on the immune system in particular on regulatory T cells. Before his move to Kiel in 2004, he held a professorship at the University Münster. He was member of the IZKF from 1998 to 2004.
Agatha Schwarz studied biology at the University Warszawa, Poland. She received her PhD at the University of Münster where she worked as a postdoc from 1991 to 2004. In 2004 she moved to the University Kiel where she is heading the Laboratory of Cell Biology at the Department of Dermatology. Her work focuses on the effect of ultraviolet radiation on the immune system in particular on regulatory T cells.
-
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
-
Research funding: Our research was funded over decades by many funding bodies including the German Research Foundation, the Interdisciplinary Center of Clinical Research of the Medical Faculty of the Westfalian-Wilhelms-University Münster, the Federal Ministry of Education and Research, the Federal Ministry of Environmental Protection, the European Community, the CERIES Award (Chanel), the Exposome Grant (Vichy).
-
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
References
Aragane, Y., Maeda, A., Schwarz, A., Tezuka, T., Ariizumi, K., and Schwarz, T. (2003). Involvement of dectin-2 in ultraviolet radiation-induced tolerance. J. Immunol. 171: 3801–3807, https://doi.org/10.4049/jimmunol.171.7.3801.Search in Google Scholar PubMed
Beissert, S., Schwarz, A., and Schwarz, T. (2006). Regulatory T cells. J. Invest. Dermatol. 126: 15–24, https://doi.org/10.1038/sj.jid.5700004.Search in Google Scholar PubMed
Belkaid, Y. and Naik, S. (2013). Compartmentalized and systemic control of tissue immunity by commensals. Nat. Immunol. 14: 646–653, https://doi.org/10.1038/ni.2604.Search in Google Scholar PubMed PubMed Central
Bruhs, A., Schwarz, T., and Schwarz, A. (2016). Prevention and mitigation of experimental autoimmune encephalomyelitis by murine beta-defensins via induction of regulatory T cells. J. Invest. Dermatol. 136: 173–181, https://doi.org/10.1038/jid.2015.405.Search in Google Scholar PubMed
Christensen, G.J. and Brüggemann, H. (2014). Bacterial skin commensals and their role as host guardians. Benef. Microbes 5: 201–215, https://doi.org/10.3920/bm2012.0062.Search in Google Scholar PubMed
Elmets, C.A., Bergstresser, P.R., Tigelaar, R.E., Wood, P.J., and Streilein, J.W. (1983). Analysis of the mechanism of unresponsiveness produced by haptens painted on skin exposed to low dose ultraviolet radiation. J. Exp. Med. 158: 781–794, https://doi.org/10.1084/jem.158.3.781.Search in Google Scholar PubMed PubMed Central
Ghoreishi, M., Bach, P., Obst, J., Komba, M., Fleet, J.C., and Dutz, J.P. (2009). Expansion of antigen-specific regulatory T cells with the topical vitamin D analog calcipotriol. J. Immunol. 182: 6071–6078, https://doi.org/10.4049/jimmunol.0804064.Search in Google Scholar PubMed PubMed Central
Gilliet, M., Conrad, C., Geiges, M., Cozzio, A., Thürlimann, W., Burg, G., Nestle, F.O., and Dummer, R. (2004). Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. Arch. Dermatol. 140: 1490–1495, https://doi.org/10.1001/archderm.140.12.1490.Search in Google Scholar PubMed
Gläser, R., Navid, F., Schuller, W., Jantschitsch, C., Harder, J., Schröder, J.M., and Schwarz, A.,T. (2009). UV-B radiation induces the expression of antimicrobial peptides in human keratinocytes in vitro and in vivo. J. Allergy Clin. Immunol. 123: 1117–1123, https://doi.org/10.1016/j.jaci.2009.01.043.Search in Google Scholar PubMed
Glass, M.J., Bergstresser, P.R., Tigelaar, R.E., and Streilein, J.W. (1990). UVB radiation and DNFB skin painting induce suppressor cells universally in mice. J. Invest. Dermatol. 94: 273–278, https://doi.org/10.1111/1523-1747.ep12874117.Search in Google Scholar PubMed
Gorman, S., Kuritzky, L.A., Judge, M.A., Dixon, K.M., McGlade, J.P., Mason, R.S., Finlay-Jones, J.J., and Hart, P.H. (2007). Topically applied 1,25-dihydroxyvitamin D3 enhances the suppressive activity of CD4+CD25+ cells in the draining lymph nodes. J. Immunol. 179: 6273–6283, https://doi.org/10.4049/jimmunol.179.9.6273.Search in Google Scholar PubMed
Kripke, M.L. (1974). Antigenicity of murine skin tumors induced by ultraviolet light. J. Natl. Cancer Inst. 53: 1333–1336, https://doi.org/10.1093/jnci/53.5.1333.Search in Google Scholar PubMed
Kripke, M.L., Lofgreen, J.S., Beard, J., Jessup, J.M., and Fisher, M.S. (1977). In vivo immune responses of mice during carcinogenesis by ultraviolet irradiation. J. Natl. Cancer Inst. 59: 1227–1230, https://doi.org/10.1093/jnci/59.4.1227.Search in Google Scholar PubMed
Maslowski, K.M., Vieira, A.T., Ng, A., Kranich, J., Sierro, F., Yu, D., Schilter, H.C., Rolph, M.S., Mackay, F., Artis, D, et al.. (2009). Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461: 1282–1286, https://doi.org/10.1038/nature08530.Search in Google Scholar PubMed PubMed Central
Mazmanian, S.K., Round, J.L., and Kasper, D.L. (2008). A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453: 620–625, https://doi.org/10.1038/nature07008.Search in Google Scholar PubMed
Naik, S., Bouladoux, N., Wilhelm, C., Molloy, M.J., Salcedo, R., Kastenmuller, W., Deming, C., Quinones, M., Koo, L., Conlan, S, et al.. (2012). Compartmentalized control of skin immunity by resident commensals. Science 337: 1115–1119, https://doi.org/10.1126/science.1225152.Search in Google Scholar PubMed PubMed Central
Navid, F., Boniotto, M., Walker, C., Ahrens, K., Proksch, E., Sparwasser, T., Müller, W., Schwarz, T., and Schwarz, A. (2012). Induction of regulatory T cells by a murine beta-defensin. J. Immunol. 188: 735–743, https://doi.org/10.4049/jimmunol.1100452.Search in Google Scholar PubMed
Ochoa-Reparaz, J., Mielcarz, D.W., Ditrio, L.E., Burroughs, A.R., Foureau, D.M., Haque-Begum, S., and Kasper, L.H. (2009). Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J. Immunol. 183: 6041–6050, https://doi.org/10.4049/jimmunol.0900747.Search in Google Scholar PubMed
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., and Toda, M. (1995). Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155: 1151–1164.Search in Google Scholar
Schwarz, A., Grabbe, S., Grosse-Heitmeyer, K., Roters, B., Riemann, H., Luger, T.A., Trinchieri, G., and Schwarz, T. (1998). Ultraviolet light-induced immune tolerance is mediated via the Fas/Fas-ligand system. J. Immunol. 160: 4262–4270.Search in Google Scholar
Schwarz, A., Beissert, S., Grosse-Heitmeyer, K., Gunzer, M., Bluestone, J.A., Grabbe, S., and Schwarz, T. (2000). Evidence for functional relevance of CTLA-4 in ultraviolet-radiation-induced tolerance. J. Immunol. 165: 1824–1831, https://doi.org/10.4049/jimmunol.165.4.1824.Search in Google Scholar PubMed
Schwarz, A., Ständer, S., Berneburg, M., Böhm, M., Kulms, D., van Steeg, H., Grosse-Heitmeyer, K., Krutmann, J., and Schwarz, T. (2002). Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair. Nat. Cell Biol. 4: 26–31, https://doi.org/10.1038/ncb717.Search in Google Scholar PubMed
Schwarz, A., Maeda, A., Wild, M.K., Kernebeck, K., Gross, N., Aragane, Y., Beissert, S., Vestweber, D., and Schwarz, T. (2004). UV-induced regulatory T cells do not only inhibit the induction but can also suppress the effector phase of contact hypersensitivity. J. Immunol. 172: 1036–1043, https://doi.org/10.4049/jimmunol.172.2.1036.Search in Google Scholar PubMed
Schwarz, A., Maeda, A., Kernebeck, K., van Steeg, H., Beissert, S., and Schwarz, T. (2005). Prevention of UV radiation-induced immunosuppression by IL-12 is dependent on DNA repair. J. Exp. Med. 201: 173–179, https://doi.org/10.1084/jem.20041212.Search in Google Scholar PubMed PubMed Central
Schwarz, A., Maeda, A., and Schwarz, T. (2007). Alteration of the migratory behavior of UV-induced regulatory T cells by tissue-specific dendritic cells. J. Immunol. 178: 877–886, https://doi.org/10.4049/jimmunol.178.2.877.Search in Google Scholar PubMed
Schwarz, T. (2008). 25 years of UV-induced immunosuppression mediated by T cells-from disregarded T suppressor cells to highly respected regulatory T cells. Photochem. Photobiol. 84: 10–18, https://doi.org/10.1111/j.1751-1097.2007.00223.x.Search in Google Scholar PubMed
Schwarz, T. (2010). The dark and the sunny sides of UVR-induced immunosuppression: photoimmunology revisited. J. Invest. Dermatol. 130: 49–54, https://doi.org/10.1038/jid.2009.217.Search in Google Scholar PubMed
Schwarz, A., Navid, F., Sparwasser, T., Clausen, B.E., and Schwarz, T. (2012). 1,25-dihydroxyvitamin D exerts similar immunosuppressive effects as UVR but is dispensable for local UVR-induced immunosuppression. J. Invest. Dermatol. 132: 2762–2769, https://doi.org/10.1038/jid.2012.238.Search in Google Scholar PubMed
Schwarz, A., Bruhs, A., and Schwarz, T. (2017). The short-chain fatty acid sodium butyrate functions as a regulator of the skin immune system. J. Invest. Dermatol. 137: 855–864, https://doi.org/10.1016/j.jid.2016.11.014.Search in Google Scholar PubMed
Schwarz, A., Philippsen, R., and Schwarz, T. (2021). Induction of regulatory T cells and correction of cytokine disbalance by short-chain fatty acids: implications for psoriasis therapy. J. Invest. Dermatol. 141: 95–104, https://doi.org/10.1016/j.jid.2020.04.031.Search in Google Scholar PubMed
Smith, P.M., Howitt, M.R., Panikov, N., Michaud, M., Gallini, C.A., Bohlooly, Y.M., Glickman, J.N., and Garrett, W.S. (2013). The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341: 569–573, https://doi.org/10.1126/science.1241165.Search in Google Scholar PubMed PubMed Central
Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T.W., and Sakaguchi, S. (2000). Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192: 303–310, https://doi.org/10.1084/jem.192.2.303.Search in Google Scholar PubMed PubMed Central
Thornton, A.M. and Shevach, E.M. (2000). Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J. Immunol. 164: 183–190, https://doi.org/10.4049/jimmunol.164.1.183.Search in Google Scholar PubMed
Toews, G.B., Bergstresser, P.R., and Streilein, J.W. (1980). Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB. J. Immunol. 124: 445–453.Search in Google Scholar
Trompette, A., Gollwitzer, E.S., Yadava, K., Sichelstiel, A.K., Sprenger, N., Ngom-Bru, C., Carine Blanchard, C., Junt, T., Nicod, L.P., Harris, N.L, et al.. (2014). Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20: 159–166, https://doi.org/10.1038/nm.3444.Search in Google Scholar PubMed
van der Fits, L., Mourits, S., Voerman, J.S., Kant, M., Boon, L., Laman, J.D., Cornelissen, F., Mus, A.M., Florencia, E., Prens, E.P, et al.. (2009). Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182: 5836–5845, https://doi.org/10.4049/jimmunol.0802999.Search in Google Scholar PubMed
© 2021 Walter de Gruyter GmbH, Berlin/Boston
