Intercellular mast cell - macrophage communication mediated by mast cell secretory granules: impact on macrophage metabolic fitness, programming and functional plasticity

• Applicant: Professorin Dr. Anne Dudeck
• Subject Area: Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456679927

Mast cells (MC) and macrophages (Mph) are both tissue-resident innate sentinel cells located in close proximity in barrier tissues. They contribute crucially to host defence, tissue integrity, and homeostasis, and have overlapping but non-redundant functions. However, the intercellular communication between MCs and Mphs, and how they influence each other's functions, is not fully understood. During the first funding period of this project, we demonstrated that Mph actively engulf intact MC granules (MCG) released during MC degranulation. This boosts Mph function, but directs them towards atypical plasticity exhibiting features of both classical and alternative activation. Consistent with this, this unique type of MCG-mediated intercellular communication triggers mixed transcriptomic and metabolic programming of Mph. Intriguingly, we confirmed that MCG-mediated MC-Mph communication occurs in human cells and tissues, inducing atypical Mph plasticity through MCG uptake as well, even in inflamed psoriatic lesions.In light of the clinical and translational significance of our findings, we aim to investigate the mechanisms and consequences of MCG uptake on Mphs, particularly with regard to metabolic programming, in more detail. We hypothesise that MCG uptake triggers gradual metabolic reprogramming associated with, or potentially causing, the functional gain and plasticity. Through the longitudinal analysis of the correlation between MCG uptake/degradation and metabolic adaptation, we intend to demonstrate how MCG functions as a vitality signal or metabolic nutrient. To this end, we will combine multiscale imaging with metabolic, proteomic and transcriptomic profiling. Additionally, we will use in vivo models of skin inflammation and wound healing to investigate how MCG-mediated MC-Mph communication, alongside other inflammatory signals, contributes to the rewiring of Mph’ plasticity, or even serves as a checkpoint to direct one or the other of their pleiotropic functions. A detailed mechanistic understanding of MC effects on the proinflammatory or regenerative properties of Mph – via MC granules as communication tool - will help to define therapeutic targets that can strengthen the host's defences or dampen excessive inflammatory responses.

• DFG Programme: Research Grants