NEXUS · Network Synergies in Tissue Homeostasis and Stromal Prevention of Inflammatory Disease.

Inflammation has evolved to protect us from the outside world. However, in doing so, it consumes large amounts of energy and causes collateral damage, thus requiring strict control on multiple levels. While the mechanisms that govern inflammation once ongoing are well defined, we lack basic knowledge of the processes that regulate its actual onset in vivo. Only by understanding the mechanisms that orchestrate tissue stress responses and defend against unwanted inflammation will we pave the way for new therapeutic approaches in future precision medicine: Not only treating inflammation once it is active, but preventing inflammatory disease from developing in the first place.I hypothesise that prevention of inflammation can be accomplished at the level of tissue homeostasis and cooperative stromal biology. The stroma that underlies any given tissue is not a passive scaffold. Instead it comprises a functional network that regulates key aspects of tissue physiology as an adaptive and self-organising system (""homeostat""). Resident tissue macrophages (RTM) - the tissue’s very own regulators of inflammation - are physically connected to this homeostat and thereby directly integrated into its cooperative signalling grid. Hard-wired communication mechanisms and synergies allow RTM-stroma networks to operate as a functional syncytium, a hitherto unknown operating system that coordinates stress responses and actively prevents the onset of inflammation. Here, I propose a pioneering tissue biology approach to decipher the stromal homeostat. By combining unique bioimaging with computational 3D reconstruction and multidimensional profiling, I will quantitatively unravel complex cell interactions to explain the mechanisms and implications of stromal network communication in a living tissue. Thereby, I aim to elucidate homeostat-operating principles and establish top-down control of inflammatory tissue checkpoints in order to apply them to clinically relevant inflammatory diseases.""