Mural cell-derived chemokines provide a protective niche to safeguard vascular macrophages and limit chronic inflammation

  • Immunity. 2023 Aug 24;S1074-7613(23)00358-8. doi: 10.1016/j.immuni.2023.08.002.
Kami Pekayvaz  1 ,  Christoph Gold  2 ,  Parandis Hoseinpour  2 ,  Anouk Engel  3 ,  Alejandro Martinez-Navarro  3 ,  Luke Eivers  3 ,  Raffaele Coletti  3 ,  Markus Joppich  4 ,  Flávio Dionísio  2 ,  Rainer Kaiser  2 ,  Lukas Tomas  2 ,  Aleksandar Janjic  5 ,  Maximilian Knott  6 ,  Fitsumbirhan Mehari  3 ,  Vivien Polewka  3 ,  Megan Kirschner  3 ,  Annegret Boda  3 ,  Leo Nicolai  2 ,  Heiko Schulz  6 ,  Anna Titova  3 ,  Badr Kilani  3 ,  Michael Lorenz  3 ,  Günter Fingerle-Rowson  7 ,  Richard Bucala  8 ,  Wolfgang Enard  5 ,  Ralf Zimmer  4 ,  Christian Weber  9 ,  Peter Libby  10 ,  Christian Schulz  2 ,  Steffen Massberg  2 ,  Konstantin Stark  11
Affiliations
  • 1. Medizinische Klinik und Poliklinik I, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany. Electronic address: [email protected].
  • 2. Medizinische Klinik und Poliklinik I, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
  • 3. Medizinische Klinik und Poliklinik I, LMU University Hospital, LMU Munich, Munich, Germany.
  • 4. Department of Informatics, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 5. Anthropology and Human Genomics, Faculty of Biology, Ludwig-Maximilians University, Munich, Germany.
  • 6. Institute of Pathology, Ludwig-Maximilian University Munich, Munich, Germany.
  • 7. Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
  • 8. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
  • 9. DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillian-Universität (LMU) München, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
  • 10. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • 11. Medizinische Klinik und Poliklinik I, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany. Electronic address: [email protected].
PMID: 37652021 DOI: 10.1016/j.immuni.2023.08.002
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.

Keywords
CCL2; MIF; atherosclerosis; chemokines; chronic inflammation; macrophages; mural cells; pericytes; smooth muscle cells; vascular macrophages.
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