Role of the metabolic adaption of macrophages during the maintenance of tissue homeostasis

Principle Investigator

Scientific interest within the context of the graduate college:

Role of tissue-resident macrophages during the maintenance of tissue homeostasis and the prevention of inflammatory disorders.

Project description:

Introduction: Tissue-resident macrophages including brain microglia, synovial macrophages and alveolar macrophages are considered essential for the maintenance of tissue homeostasis and the functionality of the respective organs.^1,2 A common feature of these cells is their capacity to constantly ingest and remove dying cells and large amounts of cellular debris that accumulate during physiological tissue turnover and tissue damage, respectively. Dysfunction of this macrophage compartment thus results in the accumulation of cell-derived danger signals and eventually triggers the development of spontaneous inflammatory and degenerative diseases.^3,4

Our previous work demonstrates that the constant requirement of an efficient phagocytic capacity imposes a substantial metabolic challenge for tissue macrophages, suggesting that metabolic adaption is a key feature of these cells.^5,6 To better understand the functional and metabolic properties of tissue-resident macrophages during steady state and inflammation, we plan to assess the specific metabolic features of individual macrophage subsets in vivo and study the impact of their capacity to metabolically adapt for tissue homeostasis and maintenance of health. We will use cutting-edge approaches including single-cell sequencing, spectral flow cytometry and fluorescence lifetime imaging (FLIM) to perform a detailed characterization of the metabolic states of macrophage subsets in vivo. Macrophage-specific conditional deletion of TFAM, an essential mitochondrial transcription factor, will allow studying the relevance of metabolic adaption of macrophages for tissue homeostasis.

Aim 1: Analysis of the metabolic properties of macrophage subsets during steady state and inflammation Using single-cell RNA sequencing as well as flow cytometry in conjunction with FLIM, we will characterize the metabolic state of tissue-resident macrophages and monocyte-derived macrophages during steady state and pulmonary inflammation.

Aim 2: Understanding the role of metabolic adaption of macrophages for the maintenance of tissue homeostasis. A conditional deletion of the transcription factor TFAM in macrophages will allow to determine the contribution of mitochondrial function and the metabolic plasticity of macrophages during the maintenance of health and prevention of inflammatory diseases.

References