Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):685-693. doi: 10.1161/ATVBAHA.119.312386.
van der Vorst, EPC; Mandl, M; Müller, M; Neideck, C; Jansen, Y; Hristov, M; Gencer, S; Peters, LJF; Meiler, S; Feld, M; Geiselhöringer, AL; de Jong, RJ; Ohnmacht, C; Noels, H; Soehnlein, O; Drechsler, M; Weber, C; Döring, Y
Institute for Cardiovascular Prevention (IPEK), LMU Munich, Germany DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany Department of Dermatology and Venereology, Hamad Medical Corporation and School of Medicine, Weill Cornell University-Qatar, Qatar University, Doha (M.F.). Center of Allergy Environment (ZAUM), Helmholtz Center and TU Munich, Neuherberg, Germany Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, Germany. Department of Physiology and Pharmacology (FyFa), Karolinska Institutet, Stockholm, Sweden. Cardiovascular Research Institute (CARIM), Maastricht University, the Netherlands.
Objective- Expression of the chemokine-like receptor ChemR23 (chemerin receptor 23) has been specifically attributed to plasmacytoid dendritic cells (pDCs) and macrophages and ChemR23 has been suggested to mediate an inflammatory immune response in these cells. Because chemokine receptors are important in perpetuating chronic inflammation, we aimed to establish the role of ChemR23-deficiency on macrophages and pDCs in atherosclerosis. Approach and Results- ChemR23-knockout/knockin mice expressing eGFP (enhanced green fluorescent protein) were generated and after crossing with apolipoprotein E-deficient ( Apoe-/- ChemR23 e/e) animals were fed a western-type diet for 4 and 12 weeks. Apoe-/- ChemR23 e/e mice displayed reduced lesion formation and reduced leukocyte adhesion to the vessel wall after 4 weeks, as well as diminished plaque growth, a decreased number of lesional macrophages with an increased proportion of M2 cells and a less inflammatory lesion composition after 12 weeks of western-type diet feeding. Hematopoietic ChemR23-deficiency similarly reduced atherosclerosis. Additional experiments revealed that ChemR23-deficiency induces an alternatively activated macrophage phenotype, an increased cholesterol efflux and a systemic reduction in pDC frequencies. Consequently, expression of the pDC marker SiglecH in atherosclerotic plaques of Apoe-/- ChemR23 e/e mice was declined. ChemR23-knockout pDCs also exhibited a reduced migratory capacity and decreased CCR (CC-type chemokine receptor)7 expression. Finally, adoptive transfer of sorted wild-type and knockout pDCs into Apoe-/- recipient mice revealed reduced accumulation of ChemR23-deficient pDCs in atherosclerotic lesions. Conclusions- Hematopoietic ChemR23-deficiency increases the proportion of alternatively activated M2 macrophages in atherosclerotic lesions and attenuates pDC homing to lymphatic organs and recruitment to atherosclerotic lesions, which synergistically restricts atherosclerotic plaque formation and progression.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 400 scientific publications are based on research using Ozgene mice.