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Thioredoxin-1 promotes anti-inflammatory macrophages of the M2 phenotype and antagonizes atherosclerosis.
El Hadri, Khadija; Mahmood, Dler Faieeq Darweesh; Couchie, Dominique; Jguirim-Souissi, Imene; Genze, Felicitas; Diderot, Vimala; Syrovets, Tatiana; Lunov, Oleg; Simmet, Thomas; Rouis, Mustapha.
Afiliação
  • El Hadri K; Unité de Recherche, UR-04, Vieillissement, Stress et Inflammation, Université Pierre et Marie Curie, Paris, France.
Arterioscler Thromb Vasc Biol ; 32(6): 1445-52, 2012 Jun.
Article em En | MEDLINE | ID: mdl-22516068
ABSTRACT

OBJECTIVE:

Oxidative stress is believed to play a key role in cardiovascular disorders. Thioredoxin (Trx) is an oxidative stress-limiting protein with anti-inflammatory and antiapoptotic properties. Here, we analyzed whether Trx-1 might exert atheroprotective effects by promoting macrophage differentiation into the M2 anti-inflammatory phenotype. METHODS AND

RESULTS:

Trx-1 at 1 µg/mL induced downregulation of p16(INK4a) and significantly promoted the polarization of anti-inflammatory M2 macrophages in macrophages exposed to interleukin (IL)-4 at 15 ng/mL or IL-4/IL-13 (10 ng/mL each) in vitro, as evidenced by the expression of the CD206 and IL-10 markers. In addition, Trx-1 induced downregulation of nuclear translocation of activator protein-1 and Ref-1, and significantly reduced the lipopolysaccharide-induced differentiation of inflammatory M1 macrophages, as indicated by the decreased expression of the M1 cytokines, tumor necrosis factor-α and monocyte chemoattractant protein-1. Consistently, Trx-1 administered to hyperlipoproteinemic ApoE2.Ki mice at 30 µg/30 g body weight challenged either with lipopolysaccharide at 30 µg/30 g body weight or with IL-4 at 500 ng/30 g body weight significantly induced the M2 phenotype while inhibiting differentiation of macrophages into the M1 phenotype in liver and thymus. ApoE2.Ki mice challenged once weekly with lipopolysaccharide for 5 weeks developed severe atherosclerotic lesions enriched with macrophages expressing predominantly M1 over M2 markers. In contrast, however, daily injections of Trx-1 shifted the phenotype pattern of lesional macrophages in these animals to predominantly M2 over M1, and the aortic lesion area was significantly reduced (from 100%±18% to 62.8%±9.8%; n=8; P<0.01). Consistently, Trx-1 colocalized with M2 but not with M1 macrophage markers in human atherosclerotic vessel specimens.

CONCLUSIONS:

The ability of Trx-1 to promote differentiation of macrophages into an alternative, anti-inflammatory phenotype may explain its protective effects in cardiovascular diseases. These data provide novel insight into the link between oxidative stress and cardiovascular diseases.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças da Aorta / Tiorredoxinas / Diferenciação Celular / Macrófagos Peritoneais / Aterosclerose / Anti-Inflamatórios Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças da Aorta / Tiorredoxinas / Diferenciação Celular / Macrófagos Peritoneais / Aterosclerose / Anti-Inflamatórios Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2012 Tipo de documento: Article