Control of immune homeostasis by metabolic pathways in macrophages

Macrophages are central cells for the maintenance of anti-inflammatory tissue integrity and the induction of proinflammatory immune responses against pathogens. These processes depend on proper macrophage activation and polarization into functionally distinct subtypes with individual effector functions. Macrophage activation and polarization is accompanied by a metabolic reconfiguration of their energy metabolism including shifts in glycolysis and mitochondrial respiration. The importance of the energy metabolism has been recognized in diseases such as diabetes, atherosclerosis, or cancer. Surprisingly, whether metabolic reconfiguration directly controls the immune response of macrophages is largely uncharacterized. The central aim of my research proposal is to investigate the role of core metabolic processes such as glycolysis, oxidative phosphorylation or the pentose phosphate pathway for macrophage activation and function. I will concentrate on the role of the mTOR pathway, a major metabolic signaling integrator, for these processes and analyze how it dictates metabolic control of immune responses and tissue homeostasis. By a combination of cutting-edge genetic, pharmacologic, and metabolomic approaches, the following questions will be addressed: 1) Which metabolic energy processes are controlled by the mTOR pathway in macrophages? 2) How does this metabolic reconfiguration contribute to macrophage polarization and effector functions such as phagocytosis? 3) Does the energy metabolism of macrophages and dendritic cells control adaptive T-cell responses? The elucidation how macrophages metabolically coordinate immune and homeostatic responses will have fundamental implications for our understanding of immunity. Assessing the metabolic role of the mTOR pathway for macrophage function will provide novel therapeutic strategies to control chronic inflammatory or immune-related disorders by rewiring the cellular energy metabolism of the innate immune system.

Macrophages are central cells for the maintenance of anti-inflammatory tissue integrity and the induction of proinflammatory immune responses against pathogens. These processes depend on proper macrophage activation and polarization into functionally distinct subtypes with individual effector functions. Macrophage activation and polarization is accompanied by a metabolic reconfiguration of their energy metabolism including shifts in glycolysis and mitochondrial respiration. The importance of the energy metabolism has been recognized in diseases such as diabetes, atherosclerosis, or cancer. Surprisingly, whether metabolic reconfiguration directly controls the immune response of macrophages was largely uncharacterized. The central aim of my research proposal was to investigate the role of core metabolic processes such as glycolysis for macrophage activation and function. We concentrated on the role of the mTOR pathway, a major metabolic signaling integrator, for these processes and analyzed how it dictates metabolic control of immune responses and tissue homeostasis. We have found that chronic activation of mTOR in macrophages leads to granulomatous disease. Activation of mTOR promoted macrophage proliferation and granulomatous lesions in mice. Interestingly, in the granulomatous disease sarcoidosis, we similarly found activation of mTOR in macrophages that was associated with chronicity. The results have now led to an ongoing clinical trial that investigates mTOR inhibitors in sarcoidosis patients. Moreover, we have discovered that the metabolic enzyme PHGDH, which is regulated my TOR, is import for specific anti-inflammatory properties of macrophages. The elucidation how macrophages metabolically coordinate immune and homeostatic responses will have fundamental implications for our understanding of immunity. Assessing the metabolic role of the mTOR pathway for macrophage function provided novel therapeutic strategies to control chronic inflammatory or immune-related disorders by rewiring the cellular energy metabolism of the innate immune system.