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Short chain fatty acids: Master regulators of cutaneous immunity and potential candidates for therapeutic interventions

短链脂肪酸：皮肤免疫的主要调节因子和治疗干预的潜在候选者

基本信息

批准号：
387426510
负责人：
Professor Dr. Thomas Schwarz
金额：
--
依托单位：
Klinik für Dermatologie, Venerologie und Allergologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/387426510?language=en
关键词：
Short chain fatty acids Master

项目摘要

There is evidence that gut commensal microbes affect the mucosal immune system via expansion of regulatory T cells (Treg) in the colon. This is mediated via short-chain fatty acids (SCFA), bacterial metabolites generated during fiber fermentation, which include butyrate, propionate, and acetate. We postulated that SCFA produced by commensal skin bacteria may also activate resident skin Treg, the activity of which is diminished in certain inflammatory dermatoses. Sodium butyrate (SB) applied topically was found to suppress allergic contact dermatitis in mice. This effect was associated with the induction/activation of Treg. A similar beneficial effect of SB was observed in imiquimod-induced inflammation, an established murine model of psoriasis-like skin inflammation. In this proposal it shall be studied whether other SCFA like propionate or acetate exert similar anti-inflammatory features. SB appears to directly affect T cells and to shift them into a regulatory phenotype. The underlying molecular mechanisms shall be clarified. In addition, it shall be studied whether SB also affects antigen-presenting cells. Topically applied SB appears to exert also systemic anti-inflammatory effects. It shall be clarified by which mechanisms SB exerts this unexpected effect by utilizing adoptive transfer experiments and transgenic mice (DEREG, HCA2-knock-out mice). To elucidate the effects of SB in the human system, biopsies from allergic contact dermatitis reactions and psoriatic plaques shall be treated ex vivo with SB and the in situ changes shall be analyzed. SB appears to reverse the mitigated activity of Treg from psoriasis patients. These preliminary observations shall be confirmed and the underlying mechanisms shall be elucidated. Together this project shall clarify whether SCFA are suitable compounds to harness Treg for anti-inflammatory purposes and be the basis for future clinical studies, finally evaluating the therapeutic potential of these compounds.

有证据表明，肠道共生微生物通过扩张结肠中的调节性T细胞(Treg)来影响粘膜免疫系统。这是通过短链脂肪酸(SCFA)介导的，短链脂肪酸是纤维发酵过程中产生的细菌代谢物，包括丁酸盐、丙酸和醋酸酯。我们推测，由共生皮肤细菌产生的SCFA也可能激活驻留的皮肤Treg，其活性在某些炎症性皮肤病中减弱。丁酸钠(SB)外用可抑制小鼠变态反应性接触性皮炎。这种作用与Treg的诱导/激活有关。SB在咪喹莫特诱导的炎症中也观察到了类似的有益效果，这是一种已建立的银屑病样皮肤炎症的小鼠模型。在这项建议中，应研究其他SCFA，如丙酸或醋酸酯是否具有类似的抗炎作用。SB似乎直接影响T细胞，并将其转变为调节性表型。应阐明其潜在的分子机制。此外，还应研究SB是否也影响抗原提呈细胞。局部使用SB似乎也有全身抗炎作用。应该阐明SB通过过继转移实验和转基因小鼠(DEREG，HCA2基因敲除小鼠)发挥这种意想不到的效果的机制。为了阐明Sb对人体系统的影响，过敏性接触性皮炎反应和银屑病斑块的活检组织应该用Sb进行体外处理，并对原位变化进行分析。SB似乎逆转了银屑病患者Treg的缓解活性。这些初步观察结果应得到证实，并应阐明其基本机制。总而言之，该项目将阐明SCFA是否适合利用Treg用于抗炎目的，并作为未来临床研究的基础，最终评估这些化合物的治疗潜力。