Leukocyte Cathepsin C Deficiency Attenuates Atherosclerotic Lesion Progression by Selective Tuning of Innate and Adaptive Immune Responses

Abstract

Objective The protein degrading activity of Cathepsin C, 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 was 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.

Neutrophil Extracellular Traps Enhance Early Inflammatory Response in Sendai Virus-Induced Asthma Phenotype

“…DPPI deficiency also attenuates early atherosclerotic lesion in LDL-receptor-deficient mice (40). A recent report established that the absence of DPPI abrogates in vitro NET formation (13).…”

Atherosclerosis

“…Recently, using this technique, it has been demonstrated that cathepsin C deficiency 62 , CD43 (an integral membrane glycoprotein), 63 CC chemokine ligand 3, 64 or angiotensin-converting enzyme (a critical enzyme to generate angiotensin II) 65 in leukocytes led to reductions of atherosclerosis in hypercholesterolemic mice at a single time point. In mice studied at multiple durations of Western diet feeding, deficiency of the common β subunit of the granulocyte macrophage colony-stimulating factor/interleukin-3 receptor in leukocytes only reduced lesion size transiently.…”

Global proteome of <em>LonP1</em>^+/- mouse embryonal fibroblasts reveals impact on respiratory chain, but no interdependence between Eral1 and mitoribosomes

“…Also, total mitochondrial biogenesis and mitophagy did not seem to be altered significantly. However, the lysosomal degradation of immunological targets was strongly upregulated together with phagocytosis and endosomal pathways, with the strongest upregulations concerning Ctsz and Ctsc which act in innate immune pathways [69,70]. Furthermore, it seemed credible furthermore that LonP1 deficiency affects the import of mitochondrial precursor proteins, since the mitochondrial import receptor Tomm70a, the import peptidase Pmpcb and the folding chaperone Hspd1 had significantly altered abundances.…”