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: Dler Faieeq Darweesh Mahmood, Amna Abderrazak, Dominique Couchie, Oleg Lunov, Vimala Diderot, Tatiana Syrovets, Mohamed-Naceur Slimane, Fabien Gosselet, Thomas Simmet, Mustapha Rouis, Khadija El Hadri
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 228 Issue 7 Pg. 1577-83 (Jul 2013) ISSN: 1097-4652 [Electronic] United States
• PMID: 23335265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters
• Apolipoprotein E2
• Biomarkers
• Lectins, C-Type
• Mannose Receptor
• Mannose-Binding Lectins
• Peptide Fragments
• Receptors, Cell Surface
• Trx80 protein, human
• Thioredoxins

Topics

• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Apolipoprotein E2 (genetics, metabolism)
• Atherosclerosis (etiology, pathology, physiopathology)
• Biomarkers (metabolism)
• Cell Differentiation
• Humans
• Inflammation (etiology, pathology, physiopathology)
• Lectins, C-Type (metabolism)
• Macrophages (classification, pathology, physiology)
• Mannose Receptor
• Mannose-Binding Lectins (metabolism)
• Mice
• Mice, Inbred C57BL
• Oxidative Stress
• Peptide Fragments (physiology)
• Phenotype
• Receptors, Cell Surface (metabolism)
• Thioredoxins (physiology)