Thioredoxin-1 promotes anti-inflammatory macrophages of the M2 phenotype and antagonizes atherosclerosis.

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.

• Authors: Khadija El Hadri, Dler Faieeq Darweesh Mahmood, Dominique Couchie, Imene Jguirim-Souissi, Felicitas Genze, Vimala Diderot, Tatiana Syrovets, Oleg Lunov, Thomas Simmet, Mustapha Rouis
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 6 Pg. 1445-52 (Jun 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22516068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Video-Audio Media)

Chemical References

• Anti-Inflammatory Agents
• Apolipoprotein E2
• Biomarkers
• Cyclin-Dependent Kinase Inhibitor p16
• Cytokines
• Inflammation Mediators
• Lectins, C-Type
• Lipopolysaccharides
• Mannose Receptor
• Mannose-Binding Lectins
• Receptors, Cell Surface
• Recombinant Proteins
• Transcription Factor AP-1
• Thioredoxins
• Apex1 protein, mouse
• DNA-(Apurinic or Apyrimidinic Site) Lyase

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Aortic Diseases (chemically induced, genetics, immunology, metabolism, pathology, prevention & control)
• Apolipoprotein E2 (genetics, metabolism)
• Atherosclerosis (chemically induced, genetics, immunology, metabolism, pathology, prevention & control)
• Biomarkers (metabolism)
• Cell Differentiation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
• Cytokines (metabolism)
• DNA-(Apurinic or Apyrimidinic Site) Lyase (metabolism)
• Disease Models, Animal
• Humans
• Inflammation Mediators (metabolism)
• Lectins, C-Type (metabolism)
• Lipopolysaccharides
• Macrophages, Peritoneal (drug effects, immunology, metabolism, pathology)
• Mannose Receptor
• Mannose-Binding Lectins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Phenotype
• Receptors, Cell Surface (metabolism)
• Recombinant Proteins (pharmacology)
• Thioredoxins (pharmacology)
• Time Factors
• Transcription Factor AP-1 (metabolism)