Targeting the cellular fatty acid metabolism in intestinal infection and inflammation

靶向免疫细胞的细胞内代谢是一种很有前途的新兴免疫调节策略。我们之前的工作表明，细胞内从头合成脂肪酸是Th17与调节性T（reg）细胞相互分化的重要代谢检查点。肠道是诱导Th17和Treg细胞的主要部位，Th17/Treg平衡的最佳调节对于正常肠道内稳态、抵抗感染和预防有害炎症至关重要。本研究的主要目的是研究细胞脂肪酸代谢的两个中心过程，即脂肪酸合成和脂肪酸氧化（FAO）对体内条件下肠道免疫反应的影响。为了实现这一目标，我们将使用已建立的和新生成的遗传小鼠模型，这些模型允许在特定免疫和非免疫细胞（包括T细胞、先天淋巴样细胞（ILC）和肠上皮细胞）中删除脂肪酸合成和FAO的关键酶。这种遗传方法将使我们能够研究体内感染和炎症条件下细胞代谢的作用，并剖析脂肪酸代谢影响肠道免疫细胞命运和功能的分子和代谢机制。此外，我们将评估使用特定抑制剂对脂肪酸代谢进行药理学调节的潜力，并通过分析从人体肠道组织分离的细胞中脂肪酸代谢的影响，将这些发现转化为人体系统。这项工作的结果不仅可能导致免疫学领域的重大概念进展，而且还将为治疗人类肠道相关的感染性和炎症性疾病提供直接的治疗前景

Targeting the intracellular metabolism of immune cells is a promising emerging strategy for immunomodulation. Our previous work suggested that intracellular de novo fatty acid synthesis represents an important metabolic checkpoint for the reciprocal differentiation of Th17 versus regulatory T(reg) cells. The intestine serves as a major site for the induction of both Th17 and Treg cells, and the optimal regulation of the Th17/Treg balance is vital for normal intestinal homeostasis, resistance against infection and prevention from detrimental inflammation. It is the main objective of this proposal to study the impact of the two central processes of the cellular fatty acid metabolism, de novo fatty acid synthesis and fatty acid oxidation (FAO), on intestinal immune responses under in vivo conditions. To achieve this goal, we will use established as well as newly generated genetic mouse models that allow for the deletion of the key enzymes of fatty acid synthesis and FAO in specific immune- and non-immune cells, including T cells, innate lymphoid cells (ILC) and intestinal epithelial cells. This genetic approach will enable us to study the role of the cellular metabolism under infectious and inflammatory conditions in vivo, and to dissect the molecular and metabolic mechanisms by which the fatty acid metabolism influences immune cell fate and function in the intestine. In addition, we will assess the potential of pharmacological modulation of the fatty acid metabolism using specific inhibitors and translate these findings into the human system by analyzing the impact of the fatty acid metabolism in cells isolated from human intestinal tissues. The results of this work may not only lead to significant conceptual advances in the field of immunology, but will also offer an immediate therapeutic perspective for the treatment of gut-associated infectious and inflammatory diseases in humans