Journal
FASEB JOURNAL
Volume 34, Issue 11, Pages 14960-14976Publisher
WILEY
DOI: 10.1096/fj.202000177R
Keywords
atherosclerosis; CD163; inflammation; TWEAK
Categories
Funding
- Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III [ISCiii/FEDER PI16/01419, PI19/00128]
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM)
- Cardiovascular Disease (CIBERCV), Spain
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Atherosclerosis is an inflammatory disease characterized by the accumulation of macrophages in the vessel wall. Macrophages depend on their polarization to exert either pro-inflammatory or anti-inflammatory effects. Macrophages of the anti-inflammatory phenotype express high levels of CD163, a scavenger receptor for the hemoglobin-haptoglobin complex. CD163 can also bind to the pro-inflammatory cytokine TWEAK. UsingApoE-deficient orApoE/CD163double-deficient mice we aim to investigate the involvement of CD163 in atherosclerosis development and its capacity to neutralize the TWEAK actions.ApoE/CD163double-deficient mice displayed a more unstable plaque phenotype characterized by an increased lipid and macrophage content, plaque size, and pro-inflammatory cytokine expression. In vitro experiments demonstrated that the absence of CD163 in M2-type macrophages-induced foam cell formation through upregulation of CD36 expression. Moreover, exogenous TWEAK administration increased atherosclerotic lesion size, lipids, and macrophages content inApoE(-/-)/CD163(-/-)compared withApoE(-/-)/CD163(+/+)mice. Treatment with recombinant CD163 was able to neutralize the proatherogenic effects of TWEAK inApoE/CD163 double-deficient mice. Recombinant CD163 abolished the pro-inflammatory actions of TWEAK on vascular smooth muscle cells, decreasing NF-kB activation, cytokines and metalloproteinases expression, and macrophages migration. In conclusion, CD163-expressing macrophages serve as a protective mechanism to prevent the deleterious effects of TWEAK on atherosclerotic plaque development and progression.
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