title: Truncated thioredoxin (Trx-80) promotes pro-inflammatory macrophages of the M1 phenotype and enhances atherosclerosis.
abstract: Vascular cells are particularly susceptible to oxidative stress that is believed to play a key role in the pathogenesis of cardiovascular disorders. Thioredoxin-1 (Trx-1) is an oxidative stress-limiting protein with anti-inflammatory and anti-apoptotic properties. In contrast, its truncated form (Trx-80) exerts pro-inflammatory effects. Here we analyzed whether Trx-80 might exert atherogenic effects by promoting macrophage differentiation into the M1 pro-inflammatory phenotype. Trx-80 at 1 µg/ml significantly attenuated the polarization of anti-inflammatory M2 macrophages induced by exposure to either IL-4 at 15 ng/ml or IL-4/IL-13 (10 ng/ml each) in vitro, as evidenced by the expression of the characteristic markers, CD206 and IL-10. By contrast, in LPS-challenged macrophages, Trx-80 significantly potentiated the differentiation into inflammatory M1 macrophages as indicated by the expression of the M1 cytokines, TNF-α and MCP-1. When Trx-80 was administered to hyperlipoproteinemic ApoE2.Ki mice at 30 µg/g body weight (b.w.) challenged either with LPS at 30 µg/30 g (b.w.) or IL-4 at 500 ng/30 g (b.w.), it significantly induced the M1 phenotype but inhibited differentiation of M2 macrophages in thymus and liver. When ApoE2.Ki mice were challenged once weekly with LPS for 5 weeks, they showed severe atherosclerotic lesions enriched with macrophages expressing predominantly M1 over M2 markers. Such effect was potentiated when mice received daily, in addition to LPS, the Trx-80. Moreover, the Trx-80 treatment led to a significantly increased aortic lesion area. The ability of Trx-80 to promote differentiation of macrophages into the classical proinflammatory phenotype may explain its atherogenic effects in cardiovascular diseases.
authors: Unité de Recherche, UR-04, Vieillissement, Stress et Inflammation, Bât. A-6è étage-Case courrier 256, Université Pierre et Marie Curie, Paris Cedex, France.
authors: Dler Faieeq Darweesh
authors: DF
authors: Mahmood
authors: Amna
authors: A
authors: Abderrazak
authors: Dominique
authors: D
authors: Couchie
authors: Oleg
authors: O
authors: Lunov
authors: Vimala
authors: V
authors: Diderot
authors: Tatiana
authors: T
authors: Syrovets
authors: Mohamed-Naceur
authors: MN
authors: Slimane
authors: Fabien
authors: F
authors: Gosselet
authors: Thomas
authors: T
authors: Simmet
authors: Mustapha
authors: M
authors: Rouis
authors: Khadija
authors: K
authors: El Hadri
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000145:classification / Q000473:pathology / Q000502:physiology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000502:physiology*; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism; D013879:Thioredoxins / Q000502:physiology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053329:Apolipoprotein E2; D015415:Biomarkers; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C427943:Trx80 protein, human; D013879:Thioredoxins