Céline Cougoule1,2, Maik Drechsler3, Indira Medina4,5, Beatriz Bermudez4,6, Rory R Koenen3, Judith Sluimer4, Ine Wolfs4, Yvonne Döring3, Veronica Herias4, Marjon Gijbels4, Ilze Bot5, Saskia de Jager5, Christian Weber3, Jack Cleutjens4, Theo J C van Berkel5, Kees-Jan Sikkink7, Atilla Mócsai8, Isabelle Maridonneau-Parini1,2, Oliver Soehnlein3,9,10, Erik A L Biessen4. 1. CNRS; IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France. 2. Université de Toulouse, Toulouse, France. 3. Institute for Prevention of Cardiovascular Prevention (IPEK), LMU Munich, Germany. 4. Experimental Vascular Pathology group, Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands. 5. Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands. 6. Department of Pharmacology, School of Pharmacy, University of Seville, Sevilla, Spain. 7. Department of Vascular Surgery, Orbis Hospital Sittard, The Netherlands. 8. Department of Physiology; Semmelweis University, Budapest, Hungary. 9. Department of Pathology, Academic Medical Center (AMC), Amsterdam, the Netherlands. 10. German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany.
Abstract
BACKGROUND: Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte-derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated. METHODS AND RESULTS: Hematopoietic Hck/Fgr-deficient, LDLr(-/-) chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage content, overt cap thinning, and necrotic core expansion as the most prominent features. Despite a Ly6C(high)-skewed proinflammatory monocyte phenotype, Hck/Fgr deficiency led to disrupted adhesion of myeloid cells to and transmigration across endothelial monolayers in vitro and atherosclerotic plaques in vivo, as assessed by intravital microscopy, flow cytometry, and histological examination of atherosclerotic arteries. Moreover, Hck/Fgr-deficient macrophages showed blunted podosome formation and mesenchymal migration capacity. In consequence, transmigrated double-knockout macrophages were seen to accumulate in the fibrous cap, potentially promoting its focal erosion, as observed for double-knockout chimeras. CONCLUSIONS: The hematopoietic deficiency of Hck and Fgr led to attenuated atherosclerotic plaque formation by abrogating endothelial adhesion and transmigration; paradoxically, it also promoted plaque instability by causing monocyte subset imbalance and subendothelial accumulation, raising a note of caution regarding src kinase-targeted intervention in plaque inflammation.
BACKGROUND: Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte-derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated. METHODS AND RESULTS: Hematopoietic Hck/Fgr-deficient, LDLr(-/-) chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage content, overt cap thinning, and necrotic core expansion as the most prominent features. Despite a Ly6C(high)-skewed proinflammatory monocyte phenotype, Hck/Fgr deficiency led to disrupted adhesion of myeloid cells to and transmigration across endothelial monolayers in vitro and atherosclerotic plaques in vivo, as assessed by intravital microscopy, flow cytometry, and histological examination of atherosclerotic arteries. Moreover, Hck/Fgr-deficient macrophages showed blunted podosome formation and mesenchymal migration capacity. In consequence, transmigrated double-knockout macrophages were seen to accumulate in the fibrous cap, potentially promoting its focal erosion, as observed for double-knockout chimeras. CONCLUSIONS: The hematopoietic deficiency of Hck and Fgr led to attenuated atherosclerotic plaque formation by abrogating endothelial adhesion and transmigration; paradoxically, it also promoted plaque instability by causing monocyte subset imbalance and subendothelial accumulation, raising a note of caution regarding src kinase-targeted intervention in plaque inflammation.
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