Myeloid cells, such as dendritic cells (DCs) and neutrophils, reside in various organs to respond to insults and are key to control immunity and inflammation. However, their aberrant activities in the elderly can cause immunosenecence and inflammaging. Different tissues comprise highly distinct milieus that impose context-dependent biochemical challenges on their resident cells, which further change when tissues age. Yet, it is not known how DCs and neutrophils survive in their different homing organs and maintain their functionality.
I hypothesize that DCs and neutrophils have to adjust their metabolism to the distinct environments of their tissues of residence. This is important, because metabolic changes upon stimulation were shown to affect the functions of those cells in vitro. Given their power to orchestrate immune responses, it is now vital to reveal the precise metabolic adaptions of DCs and neutrophils to their distinct homing organs and to determine how that affects their activities. This pioneering knowledge will expose organ-dependent metabolic vulnerabilities of DCs and neutrophils to uphold their homeostatic and immune functions, which I envisage to cause their dysfunction in aging. I will uncover the metabolic adaptions of DCs and neutrophils to >10 healthy and aged tissues using independent innovative approaches and adapted cutting-edge techniques. I will reveal the relevance of such tissue-dependent metabolic adjustments for their presence and functions in organs, and dissect the underlying molecular mechanisms. I will expose the tissue-specificity of DC and neutrophil dysfunction in aging and the role of their metabolism.
The discovery of tissue-dependent metabolic adaptions by DCs and neutrophils that impact their functions will transform translational immunology research to integrate the tissue-context and reveal novel organ-specific therapeutic strategies to combat immune dysfunction in aging and beyond.
