Häselbarth Lukas, Ouwens D Margriet, Teichweyde Nadine, Hochrath Katrin, Merches Katja, Esser Charlotte
IUF - Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, 40225 Düsseldorf, Germany.
German Diabetes Research Center, Auf´m Hennekamp 65, 40225 Düsseldorf, Germany.
EXCLI J. 2020 Mar 9;19:334-350. doi: 10.17179/excli2020-1123. eCollection 2020.
The metabolic requirements change during cell proliferation and differentiation. Upon antigen-stimulation, effector T cells switch from adenosine-triphospate (ATP)-production by oxidative phosphorylation in the mitochondria to glycolysis. In the gut it was shown that short chain fatty acids (SCFA), fermentation products of the microbiota in colon, ameliorate inflammatory reactions by supporting the differentiation of regulatory T cells. SCFA are a major energy source, but they are also anabolic metabolites, histone-deacetylase-inhibitors and activators of G protein receptors. Recently, it was reported that a topical application of the SCFA butyrate promotes regulatory T cells in the skin. Here we ask if the SCFA butyrate, propionate and acetate affect the energy metabolism and inflammatory potential of dendritic epidermal T cells (DETC), the innate resident skin γδ T cell population. Using the Seahorse™ technology, we measured glycolysis and oxidative phosphorylation (OXPHOS) in a murine DETC cell line, 7-17, upon TCR-stimulation by CD3/CD28 crosslinking, with or without SCFA addition. TCR engagement resulted in a change of the ratio glycolysis/OXPHOS. A similar metabolic shift has been described for activated CD4 T cells. Addition of 5 mM SCFA, in particular butyrate, antagonized the effect. Stimulated DETC secrete cytokines, e.g. the pro-inflammatory cytokine interferon-gamma (IFNγ), and thereby regulate skin homeostasis. Addition of butyrate and propionate to the cultures at non-toxic concentrations decreased secretion of IFNγ by DETC and increased the expression of the immunoregulatory surface receptor CD69. We hypothesize that SCFA can dampen the inflammatory activity of DETC.
细胞增殖和分化过程中代谢需求会发生变化。受到抗原刺激后，效应T细胞会从通过线粒体氧化磷酸化产生三磷酸腺苷（ATP）转变为糖酵解。在肠道中，研究表明结肠中微生物群的发酵产物短链脂肪酸（SCFA）通过支持调节性T细胞的分化来改善炎症反应。SCFA是主要的能量来源，但它们也是合成代谢产物、组蛋白去乙酰化酶抑制剂和G蛋白受体激活剂。最近有报道称，局部应用SCFA丁酸可促进皮肤中的调节性T细胞。在此，我们探讨SCFA丁酸、丙酸和乙酸是否会影响树突状表皮T细胞（DETC）的能量代谢和炎症潜能，DETC是皮肤中固有驻留的γδT细胞群体。我们使用海马（Seahorse™）技术，在有或没有添加SCFA的情况下，通过CD3/CD28交联刺激TCR，测量了小鼠DETC细胞系7-17中的糖酵解和氧化磷酸化（OXPHOS）。TCR激活导致糖酵解/OXPHOS比值发生变化。活化的CD4 T细胞也有类似的代谢转变。添加5 mM SCFA，尤其是丁酸，可拮抗这种效应。受刺激的DETC会分泌细胞因子，例如促炎细胞因子干扰素-γ（IFNγ），从而调节皮肤稳态。以无毒浓度向培养物中添加丁酸和丙酸可减少DETC分泌IFNγ，并增加免疫调节表面受体CD69的表达。我们推测SCFA可抑制DETC的炎症活性。
