Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment
| Autor: | Renske J. de Jong, Barbara Walzog, Christian Weber, Robert Pick, Almudena Ortega-Gomez, Patricia Lemnitzer, Jochen Grommes, Wolfgang Siess, Remco T. A. Megens, Janina Jamasbi, Christoph Scheiermann, Alexander Zarbock, Jan Rossaint, Janine Brauner, Maik Drechsler, Jessica Tilgner, Oliver Soehnlein, Yvonne Döring, Christine T. N. Pham, Melanie Salvermoser |
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| Přispěvatelé: | Pathology, Biomedische Technologie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, Biochemie, Pathologie |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology Myeloid Myeloid Cells/immunology/metabolism cathepsin G Integrins/metabolism 030204 cardiovascular system & hematology Cathepsin G chemistry.chemical_compound Mice 0302 clinical medicine Venules Cathepsin G/antagonists & inhibitors/genetics/metabolism Medicine Myeloid Cells Chemokine CCL5 Mice Knockout Chemotaxis Arteries focal adhesions medicine.anatomical_structure Atherosclerosis/drug therapy/etiology/metabolism/pathology medicine.symptom Cardiology and Cardiovascular Medicine Shear Strength Intravital microscopy Chemokine CCL5/genetics/metabolism Protein Binding medicine.medical_specialty Cell Adhesion/genetics Knockout Context (language use) Inflammation Article Microcirculation Vascular/metabolism/pathology Focal adhesion 03 medical and health sciences Physiology (medical) Cell Adhesion Animals Humans Leukocyte Rolling Endothelium Cell adhesion business.industry Animal Disease Models Animal 030104 developmental biology chemistry Immunology Disease Models integrins Endothelium Vascular Chemotaxis/genetics/immunology atherosclerosis business Biomarkers |
| Zdroj: | Circulation, Vol. 134, No 16 (2016) pp. 1176-1188 Circulation, 134(16), 1176-1188. Lippincott Williams and Wilkins Circulation, 134(16), 1176-1188. LIPPINCOTT WILLIAMS & WILKINS |
| ISSN: | 0009-7322 |
| Popis: | Background: Therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis has been disappointing in clinical studies. Reasons for such failures include the lack of knowledge of arterial-specific recruitment patterns. Here we establish the importance of the cathepsin G (CatG) in the context of arterial myeloid cell recruitment. Methods: Intravital microscopy of the carotid artery, the jugular vein, and cremasteric arterioles and venules in Apoe –/– and CatG-deficient mice ( Apoe –/– Ctsg –/– ) was used to study site-specific myeloid cell behavior after high-fat diet feeding or tumor necrosis factor stimulation. Atherosclerosis development was assessed in aortic root sections after 4 weeks of high-fat diet, whereas lung inflammation was assessed after inhalation of lipopolysaccharide. Endothelial deposition of CatG and CCL5 was quantified in whole-mount preparations using 2-photon and confocal microscopy. Results: Our observations elucidated a crucial role for CatG during arterial leukocyte adhesion, an effect not found during venular adhesion. Consequently, CatG deficiency attenuates atherosclerosis but not acute lung inflammation. Mechanistically, CatG is immobilized on arterial endothelium where it activates leukocytes to firmly adhere engaging integrin clustering, a process of crucial importance to achieve effective adherence under high-shear flow. Therapeutic neutralization of CatG specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of CatG-neutralizing antibodies permitted inhibition of atherogenesis in mice. Conclusions: Taken together, these findings present evidence of an arterial-specific recruitment pattern centered on CatG-instructed adhesion strengthening. The inhibition of this process could provide a novel strategy for treatment of arterial inflammation with limited side effects. |
| Databáze: | OpenAIRE |
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