Metabolic programming of human macrophages in granulomatous skin inflammation

近年来，巨噬细胞免疫代谢已成为一个新兴的、令人兴奋的科学领域。我们现在了解到，免疫信号级联和代谢途径之间存在着一种基本的相互作用，这种相互作用对M蛋白介导的免疫具有关键的调节作用。因此，该领域的总体共识是靶向免疫代谢具有巨大的转化应用潜力。然而，我们的初步数据和一些已发表的关于这一主题的研究表明，人类免疫代谢的原理和机制与小鼠免疫代谢的报道存在重大差异。因此，人类代谢的生物学仍然不明确。我们在这里询问调节人类M -代谢的途径，以及代谢如何反过来塑造人类M -表型和功能活性。为了解决我们的问题，我们建议研究原代细胞培养和人类肉芽肿性皮肤病。我们的目标是定义人类炎症性M -的生物能量谱，特别是描述糖酵解和糖酵解相关途径在人类炎症性M -中的作用。此外，我们建议使用大量和单细胞mRNA测序分析，以及肉芽肿病患者血液和皮肤样本的代谢组学来确定M -糖酵解和相关途径在这些疾病的病理生理中的作用。由于我们的单细胞RNA测序数据将包括皮肤中存在的所有免疫细胞的转录组，这些结果将为M的代谢谱提供证据，因为它与本提案中概述的目标有关，同时也为探索M和其他免疫细胞的其他代谢途径开辟了新的令人兴奋的途径。这是一个巨大的临床需求，因为肉芽肿性疾病，由结核浸润定义，总的来说是频繁的，经常误诊，通常难以治疗。在这方面，详细了解人类免疫代谢和皮肤肉芽肿病的病理生理，对于发现新的疾病分类、诊断以及确定人类疾病的治疗靶点具有巨大的潜力。

In the past years, macrophage (Mᶲ) immunometabolism has emerged as a novel exciting scientific field. We now understand that there is a fundamental cross talk of immune signaling cascades and metabolic pathways critically regulating Mᶲ-mediated immunity. Thus, there is overall consensus in the field that targeting immunometabolism offers great potential for translational applications. However, our preliminary data and few published studies on this topic point to critical differences in principles and mechanisms of immunometabolism in human Mᶲ to those reported in mice. Thus, the biology of human Mᶲ metabolism remains poorly defined. We here ask about pathways that regulate human Mᶲ metabolism and how, in turn, metabolism shapes Mᶲ phenotypes and functional activity in humans. To address our questions, we propose studying primary cell cultures and human granulomatous skin diseases. We aim to define the bio-energetic profile of human inflammatory Mᶲ and, in particular, delineate the role of glycolysis and glycolysis-related pathways in human inflammatory Mᶲ. Furthermore, we propose using bulk and single cell mRNA sequencing analyses, as well as metabolomics of blood and skin samples from patients with granulomatous disease to define the role of Mᶲ glycolysis and related pathways in the pathophysiology of these conditions. Because our single cell RNA sequencing data will include transcriptomes of all immune cells present in the skin, these results will both provide evidence of the metabolic profile of Mᶲ as it pertains to the aims outlined in this proposal, as well as opening up new exciting avenues of exploration into other metabolic pathways in Mᶲ and other immune cells. There is a great clinical need, because granulomatous diseases, which are defined by Mᶲ infiltrates, in sum are frequent, regularly misdiagnosed and typically difficult to treat. In this regard, a detailed understanding of human Mᶲ immunometabolism and the pathophysiology of cutaneous granulomatoses carries great potential for uncovering novel disease classifications, for diagnostics, as well as for identifying therapeutic targets in human diseases.