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Increased levels of the anti-inflammatory peptide Catestatin (CST), a cleavage product of the pro-hormone chromogranin A, correlate with less severe outcomes in hypertension, colitis, and diabetes. However, it is unknown how CST reduces the infiltration of monocytes and macrophages (Mϕs) in inflamed tissues. Here, it is reported that CST blocks leukocyte migration toward inflammatory chemokines. By in vitro and in vivo migration assays, it is shown that although CST itself is chemotactic, it blocks migration of monocytes and neutrophils to inflammatory attracting factor CC-chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, it directs CX 3 CR1 + Mϕs away from pancreatic islets. These findings suggest that the anti-inflammatory actions of CST are partly caused by its regulation of chemotaxis., (© 2021 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.)

Angiogenesis, the growth of new blood vessels, is a complex process requiring the orchestration of numerous different cell types, growth factors, and chemokines. Some of the recently acknowledged actors in this process are immune cells. They accumulate at hypoxic sites, but the kinetics, dynamics, and regulation of that trafficking are unknown. In this study, we used intravital and live cell imaging to understand how neutrophils and macrophages migrate and behave at angiogenic sites. We developed two reproducible models of angiogenesis: one by transplanting isolated and hypoxic pancreatic islets into the cremaster muscles of mice, and another by in vitro coculturing of mouse aortic rings with neutrophils. In vivo imaging of the hypoxic site revealed recruitment of neutrophils and macrophages, which occurred in parallel, with depletion of one subset not affecting the accumulation of the other. We found, by cell tracking and statistical analyses, that neutrophils migrated in a directional manner to "angiogenic hotspots" around the islet where endothelial sprouting occurs, which was confirmed in the in vitro model of angiogenesis and is dependent on CXCL12 signaling. Intimate interactions between neutrophils and neovessels were prevalent, and neutrophil depletion greatly hampered vessel growth. Macrophages were less motile and attained supportive positions around the neovessels. Here, we present two novel in vivo and in vitro imaging models to study leukocyte behavior and actions during angiogenesis. These models unveiled that neutrophil migration at a hypoxic site was guided by signals emanating from sprouting endothelium where these immune cells gathered at "angiogenic hotspots" at which vascular growth occurred., (© Society for Leukocyte Biology.)