Leukocyte cathepsin C deficiency attenuates atherosclerotic lesion progression by selective tuning of innate and adaptive immune responses.
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.


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.
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.).
Veronica
V
Herías
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.).
Erik A L
EA
Biessen
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.).
Cora
C
Beckers
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.).
Dianne
D
Delsing
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.).
Mengyang
M
Liao
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.).
Mat J
MJ
Daemen
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.).
Christine C T N
CC
Pham
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.
Sylvia
S
Heeneman
D056704:Adaptive Immunity; D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D002340:Carotid Artery Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D005487:Foam Cells / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007962:Leukocytes / Q000201:enzymology* / Q000276:immunology; D008262:Macrophage Activation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000201:enzymology / Q000276:immunology; D013997:Time Factors
D011973:Receptors, LDL; C533918:CTSC protein, human; D020789:Cathepsin C; C533919:Ctsc protein, mouse
atherosclerosis; human; inflammation; mice; protease