Augmented levels of CD44 in macrophages from atherosclerotic subjects: A possible IL-6–CD44 feedback loop?

The cell-adhesion molecule CD44 likely participates in atherosclerosis development. We have shown previously that pro-inflammatory cytokines affect CD44 expression. Therefore, this work examined the role of elevated CD44 levels in human macrophages. Macrophages from human atherosclerotic subjects (n = 15) showed elevated levels of CD44 transcript and protein (1.5-fold) compared to matched controls (n = 15) (P = 0.050 and 0.044, respectively). To test whether genetic factors influence CD44 expression, two single nucleotide polymorphisms in the CD44 gene were analyzed but these were not associated with coronary artery disease. We also examined the potential connection between plasma cytokine levels and CD44 expression. In atherosclerotic subjects, elevated CD44 expression correlates (P = 0.012) with enhanced macrophage IL-6 secretion (3.13 ± 2.5 pg/mL versus 0.32 ± 0.16 pg/mL in controls, P = 0.021). Additionally, CD44-deficient mice exhibit less circulating IL-6 than wild-type controls (9.8 ± 0.7 pg/mL versus 14.3 ± 0.7 pg/mL; P = 0.032). Furthermore, IL-6 augments CD44 expression in primary human macrophages after 24 h (P = 0.038) and 48 h (P = 0.015). Taken together, our data show an IL-6–CD44 feedback loop in macrophages. Such a positive feedback loop may aggravate atherosclerosis development.