Veronica Herías1, Erik A L Biessen1, Cora Beckers1, Dianne Delsing1, Mengyang Liao1, Mat J Daemen1, Christine C T N Pham1, Sylvia Heeneman2. 1. From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.). 2. From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.). s.heeneman@maastrichtuniversity.nl.
Abstract
OBJECTIVE: The protein degrading activity of cathepsin C (CatC), combined with its role in leukocyte granule activation, suggests a contribution of this cystein protease in atherosclerosis. However, no experimental data are available to validate this concept. APPROACH AND RESULTS: CatC gene and protein expression were increased in ruptured versus advanced stable human carotid artery lesions. To assess causal involvement of CatC in plaque progression and stability, we generated LDLr(-/-)//CatC(-/-) chimeras by bone marrow transplantation. CatC(-/-) chimeras presented attenuated plaque burden in carotids, descending aorta, aortic arch and root, at both the early and advanced plaque stage. CatC was abundantly expressed by plaque macrophages and foam cells. CatC expression and activity were dramatically downregulated in plaques of CatC(-/-) chimeras, supporting a hematopoietic origin of plaque CatC. Our studies unveiled an unexpected feedback of CatC deficiency on macrophage activation programs and T helper cell differentiation in as much as that CatC expression was upregulated in M1 macrophages, whereas its deficiency led to combined M2 (in vitro) and Th2 polarization (in vivo). CONCLUSIONS: Our data implicate CatC has a role in the selective tuning of innate and adaptive immune responses, relevant to a chronic immune disease, such as atherosclerosis.
OBJECTIVE: The protein degrading activity of cathepsin C (CatC), combined with its role in leukocyte granule activation, suggests a contribution of this cystein protease in atherosclerosis. However, no experimental data are available to validate this concept. APPROACH AND RESULTS:CatC gene and protein expression were increased in ruptured versus advanced stable human carotid artery lesions. To assess causal involvement of CatC in plaque progression and stability, we generated LDLr(-/-)//CatC(-/-) chimeras by bone marrow transplantation. CatC(-/-) chimeras presented attenuated plaque burden in carotids, descending aorta, aortic arch and root, at both the early and advanced plaque stage. CatC was abundantly expressed by plaque macrophages and foam cells. CatC expression and activity were dramatically downregulated in plaques of CatC(-/-) chimeras, supporting a hematopoietic origin of plaque CatC. Our studies unveiled an unexpected feedback of CatC deficiency on macrophage activation programs and T helper cell differentiation in as much as that CatC expression was upregulated in M1 macrophages, whereas its deficiency led to combined M2 (in vitro) and Th2 polarization (in vivo). CONCLUSIONS: Our data implicate CatC has a role in the selective tuning of innate and adaptive immune responses, relevant to a chronic immune disease, such as atherosclerosis.
Authors: E Lutgens; S P M Lutgens; B C G Faber; S Heeneman; M M J Gijbels; M P J de Winther; P Frederik; I van der Made; A Daugherty; A M Sijbers; A Fisher; C J Long; P Saftig; D Black; M J A P Daemen; K B J M Cleutjens Journal: Circulation Date: 2005-12-19 Impact factor: 29.690
Authors: R de Nooijer; C J N Verkleij; J H von der Thüsen; J W Jukema; E E van der Wall; Thüsen J C van Berkel; A H Baker; E A L Biessen Journal: Arterioscler Thromb Vasc Biol Date: 2005-11-23 Impact factor: 8.311
Authors: A Susanne M Zadelaar; Jan H von der Thüsen; Lianne S M Boesten; Rob C Hoeben; Mark M Kockx; Marjan A Versnel; Theo J C van Berkel; Louis M Havekes; Erik A L Biessen; Bart J M van Vlijmen Journal: Atherosclerosis Date: 2005-05-31 Impact factor: 5.162