Role Of The C-C Motif Chemokine Receptor 5 (CCR5) Polymorphism In A Mouse Model Of Kawasaki Disease-Induced Vasculitis

Introduction: Kawasaki disease (KD) is the most common form of vasculitis in young children. However, the etiology and the vulnerability of vasculitis are still enigmatic. In children, polymorphisms in CCR5 influence KD susceptibility and cardiovascular outcome, but the mechanisms are unclear. Therefore, the use of murine models is an attractive strategy to evaluate the interface between immune system and vasculitis in KD. We aimed to explore the mechanisms by which polymorphisms in CCR5 aggravates the vascular injury in KD by using the Candida albicans water soluble (CAWS) fraction model. Methods: Male (6-10-weeks-old) CCR5 deficient mice (CCR5 -/- ) and their counterpart (CCR5 +/+ ) were used. Results: After 28 days of CAWS treatment, CCL5 and CCR5 levels were increased in plasma [(pg/mL) CCR5 +/+ : 5.01 ± 0.7 n=5 vs . CCR5 +/+ CAWS: 18.71 ± 1.4* n=4, *p<0.05], and heart (14-fold changes) of CCR5 +/+ , which was associated with a clear vasculitis in coronary and AA, as well as cardiac senescence (p21 expression), cell death (caspase-3 levels), and higher contractility to norepinephrine (NA) in AA [(mN) CCR5 +/+ : 3.60 ± 0.3 n=4 vs . CCR5 +/+ CAWS: 5.72 ± 0.2* n=4, *p<0.05]. Remarkably, CCR5 -/- displayed a worse vasculitis level, further accumulation of cardiac p21 and caspase-3, and an exacerbated vascular response to NA (CCR5 -/- -CAWS: 6.70 ± 0.4 # n=5, # p<0.05 vs . CCR5 +/+ CAWS). To understand the mechanisms, we performed a plasma proteome profile cytokine assay, which revealed that KD elevates the levels of various inflammatory mediators (IL-1β, IL-6, IL-17, and TNFα) and chemokines (CXCL2, 10, 11, 19, 12, and 13 and CCL2, 3, and 4), which were exacerbated in CCR5 -/- . Yet, CAWS induced an increase in cardiac neutrophil infiltration in CCR5 +/+ [(% in relation to 10 ^ 6 leukocytes) CCR5 +/+ : 2.5 ± 1.7 n=4 vs . CCR5 +/+ CAWS: 16.1 ± 3.2* n=4, *p<0.05], which was worsened in CCR5 -/- (CCR5 -/- -CAWS: 30.2 ± 7.4 # n=4, # p<0.05 vs . CCR5 +/+ CAWS). Conclusion: Deficiency in CCR5 aggravates the vasculitis levels and cardiovascular outcomes likely regulating neutrophil infiltration and cytokines production. Therefore, children with polymorphism in CCR5 might be more susceptible in developing a severe vasculitis during KD.