Abstract 392: C-C Chemokine Receptor Type 5 Deficiency Exacerbates The Severity Of Vasculitis In A Mouse Model Of Kawasaki Disease

Abstract

Kawasaki disease (KD) is an acute vasculitis and a common cause of acquired heart disease in children. C-C chemokine receptor type 5 (CCR5) is a receptor involved in the resolution of inflammation by eliminating chemical mediators and recruiting anti-inflammatory cells into the inflammatory site. Whether CCR5 plays a vascular protective effect in KD, it is still to be clarified. We tested the hypothesis that CCR5 reduces the vasculitis by decreasing the chemokine and cytokine vascular signaling. KD was induced by the Candida albicans water-soluble fraction model (CAWS, 4mg per injection/day for 5 days) in male control (CCR5+/+) and CCR5 deficient (CCR5-/-) mice. Mice were divided in 3 CAWS treatment groups: 1 single CAWS injection(G1) to identify the chemokines and cytokines levels, 2-days post CAWS treatment (G7) to understand the acute effects of KD, and 28-days post CAWS treatment (G28) to study the chronic effects of KD. Heart and abdominal aorta (AA) were harvested for vascular characterization. We found 4 to 10-times fold increase in C-C Motif Chemokine Ligand (CCL) 1, 3, and 5 (CCR5 ligands) and CCR5 gene expression in hearts and AA from CCR5+/+ in G1. Circulating IL1β and CCL5 levels were elevated in CCR5+/+ G1, which was worsened in CCR5-/-, this pattern persisted in G7 and G28, but in less intensity. No sign of vasculitis in coronary arteries and aortic root (scored by immune cells infiltration) or abdominal aorta aneurysm (AAA) were detected in G7 in CCR5+/+ and CCR5-/-, but a vascular dysfunction, reduced relaxation to acetylcholine and increased contractility to thromboxane in AA, was found, such changes were pronounced in CCR5-/-[Maximal response (mN): CCR5+/+: 4.65 ± 0.2; CCR5+/+ G7: 6.795 ± 0.3*; CCR5-/- G7: 9.750 ± 0.7 # , *P<0.05 vs CCR5+/+; # P<0.05 vs CCR5+/+ G1]. Vasculitis in coronary arteries, aortic root, AAA formation, and a drastic loss of vascular contractility in AA were observed in CCR5+/+ and CCR5-/- G28 but was more exacerbated in later.Initial data show that CCR5 plays a protective role in the genesis of vasculitis in a mouse model of KD by regulating the chemokines and cytokines availability and signaling. For future directions, we hope to identify the vascular signaling activated by this intensified availability of chemokines and cytokines.