Metabolic programming of human macrophages in granulomatous skin inflammation

点击翻译按钮获取中文摘要

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.