Mural cell-derived chemokines provide a protective niche to safeguard vascular macrophages and limit chronic inflammation
Kami Pekayvaz, Christoph Gold, Parandis Hoseinpour, Anouk Engel, Alejandro Martinez-Navarro, Luke Eivers, Raffaele Coletti, Markus Joppich, Flávio Dionísio, Rainer Kaiser, Lukas Tomas, Aleksandar Janjic, Maximilian M. L. Knott, Fitsumbirhan T. Mehari, Vivien Polewka, Megan Kirschner, Annegret Boda, Leo Nicolai, Heiko Schulz, Anna Titova, Badr Kilani, Michael Lorenz, Günter Fingerle‐Rowson, Richard Bucala, Wolfgang Enard, Ralf Zimmer, Christian Weber, Peter Libby, Christian Schulz, Steffen Maßberg, Konstantin Stark
Abstract
Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages. Intravital imaging revealed a spatiotemporal macrophage niche across vascular beds alongside mural cells (MCs)-pericytes and smooth muscle cells. Single-cell transcriptomics, co-culture, and genetic deletion experiments revealed MC-derived expression of the chemokines CCL2 and MIF, which actively preserved macrophage survival and their homeostatic functions. In atherosclerosis, this positioned macrophages in viable plaque areas, away from the necrotic core, and maintained a homeostatic macrophage phenotype. Disruption of this MC-macrophage unit via MC-specific deletion of these chemokines triggered detrimental macrophage relocalizing, exacerbated plaque necrosis, inflammation, and atheroprogression. In line, CCL2 inhibition at advanced stages of atherosclerosis showed detrimental effects. This work presents a MC-driven safeguard toward maintaining the homeostatic vascular macrophage niche.