Mast cell communication and collaboration with macrophages – impact on severity, course and resolution of inflammation

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Mast cells (MC) and macrophages (Mph) are both tissue resident sentinel cells equipped with a plethora of sensing receptors but distinct effector functions, and reside in close proximity in peripheral tissues such as the skin. Using intravital 2-photon microscopy of transgenic MC/Mph double reporter mice, we recently detected an alternate positioning and physical interaction between MCs and Mphs at dermal blood vessels. Additionally, Mphs engulf intact MC granules exocytosed by MC degranulation upon skin inflammation. Our findings let us hypothesize that MCs and Mph dynamically communicate in healthy and inflammatory conditions and may collaborate in the recruitment of additional effector immune cells upon skin inflammation. This interaction may impact on Mph plasticity and function in the acute phase but also in the resolution of skin inflammation. Importantly, MCs may modulate Mph polarization and functionality by three modes of action: release of soluble mediators; physical contact and dynamic interaction; and sensing and uptake of intact MC granules. In this proposal, we aim to determine the spatiotemporal distribution of MC/Mph communication in the skin under physiologic and inflammatory conditions. Furthermore, we will investigate how MCs modulate Mph plasticity and functions in innate and adaptive immune responses upon contact hypersensitivity and in the resolution of inflammation. Finally we aim to detail mechanisms of MC effects on Mph polarization and function depending on the different modes of communication.