Macrophages can sense and regulate the response to tissue stresses in the absence of infection or other classical immune challenges. Recently, these cells have been identified to impact systemic blood pressure regulation by responding to tissue-born NaCl stores with transcriptional responses, leading to the remodeling of lymphatics in the periphery by inducing lymph angiogenesis. Furthermore, excess salt storage in the skin contributes to the onset of pro-inflammatory effector functions of macrophages in pathogen defense. And while the gut is the main site for salt absorption, it is highly sensitive to extra salt amounts and the subsequent microbiota changes. Moreover, we have recently discovered that macrophage cell lines and bone marrow-derived macrophages migrate chemotactically in response to salt gradients in vitro. Thus, this project aims to identify the physiologically important myeloid populations that respond to excess NaCl in the skin and the gut by altering their inflammatory signaling and migratory behavior. We will identify the underlying molecular mechanisms by performing cell sorting and transcriptomic analyses and furthermore analyze salt-modulated pathways in macrophages, which affect their inflammatory differentiation, migratory dynamics, and localization in the organ, as well as the triggering of hypersensitive reactions in the skin and the gut.