Peripheral Artery Disease Is Associated With a High CD163/TWEAK Plasma Ratio

Abstract

In addition to its role in the clearance of haptoglobin-hemoglobin (Hp-Hb) complexes, CD163 is a macrophage scavenger receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK). We recently reported that the CD163/TWEAK plasma ratio could be a potential biomarker of atherothrombosis in asymptomatic subjects. In this study, we assessed soluble TWEAK (sTWEAK) and soluble CD163 (sCD163) plasma levels in white males with peripheral artery disease (PAD) and in atherothrombotic femoral plaques to evaluate their relationship with disease. We also analyzed whether Hp-Hb complexes could compete for CD163-mediated TWEAK uptake. Patients with PAD (n=155) showed a trend toward lower sTWEAK (median [interquartile range]: 134 [110-204] versus 147 [119-205] pg/mL; P=0.067) and higher sCD163 (median [interquartile range]: 367 [269-506] versus 288 [234-369] ng/mL; P<0.001) plasma concentrations than age-matched controls (n=251). sCD163 and sTWEAK plasma levels were negatively correlated in both patients and controls. After stratification according to the severity of disease, sCD163/sTWEAK ratio was significantly increased in patients with more severe disease relative to the other groups (P=0.049). Analysis of conditioned medium obtained from cultured human atherothrombotic femoral plaque samples (n=36) and healthy aortas (n=14) revealed that high amounts of sCD163 were released by the atherothrombotic tissue, whereas sTWEAK presented the opposite trend (P<0.05). Finally, we report a potential association between CD163 shedding and oxidative stress. Our results suggest that the sCD163/sTWEAK plasma ratio may be associated with atherothrombosis burden in PAD. We hypothesize that an imbalance between TWEAK and CD163 could reflect the progression of atherothrombosis.