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

肥大细胞(MC)和巨噬细胞(MPH)都是驻留在组织中的前哨细胞，它们都配备了大量的感觉受体，但具有不同的效应功能，它们位于皮肤等周围组织中。利用转基因MC/MPH双报告基因小鼠的活体双光子显微镜，我们最近检测到MC和MPHS在真皮血管上的交替定位和物理相互作用。此外，MPHS吞噬了皮肤炎症时MC脱颗粒排出的完整MC颗粒。我们的发现让我们假设MCs和MPH在健康和炎症条件下动态交流，并可能在皮肤炎症时协作招募额外的效应器免疫细胞。这种相互作用可能会影响MPH在急性期的可塑性和功能，但也会影响皮肤炎症的消退。重要的是，MC可能通过三种作用模式调节MPH极化和功能：释放可溶性介质；物理接触和动态相互作用；感知和摄取完整的MC颗粒。在这项建议中，我们的目标是确定生理和炎症条件下皮肤MC/MPH通讯的时空分布。此外，我们将研究MCs如何在接触超敏反应和炎症消退时调节MPH的可塑性和在先天和获得性免疫反应中的功能。最后，我们将根据不同的通讯模式，详细阐述MC对PMH极化和功能的影响机制。

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.