C-C Chemokine Receptor Type 5 regulates the levels of vasculitis and vascular dysfunction in a murine model Kawasaki Disease via adjusting the IL-6 formation
Authors: Alves Juliano , Costa Rafael , Awata Wanessa , Singh Shubhnita , Bruder-Nascimento Ariane , Barbosa Gabriela , Bruder-Nascimento Thiago 
Published: May 2023

Introduction: Kawasaki disease (KD) is a form of vasculitis characterized inflammation of the blood vessels. It is the most common cause of acquired cardiovascular disease in children and its etiology is unknown. The chemokine C-C motif receptor 5 (CCR5) is broadly studied in infectious diseases and its polymorphism can influence the KD susceptibility and severity of vasculitis. However, the molecular and cellular mechanisms are still ill defined. We sought to test the hypothesis that deficiency in CCR5 exacerbates the vasculitis and vascular dysfunction in KD via dysregulating IL-6 production. Methods: We used a well-established murine model of KD, the Candida albicans water soluble (CAWS) fraction model. 5-6 weeks old male CCR5 deficient mice (CCR5-/-) and their counterparts (CCR5+/+) were used. Mice were injected with 4 mg CAWS for 5 consecutive days (d) and separated into 4 groups: CCR5+/+-Vehicle (Ctrl), CCR5+/+-CAWS (KD), CCR5-/--Vehicle (CCR5+/+ Ctrl) and CCR5-/--CAWS (CCR5-/- KD). Serum, hearts, and aortae were harvested post 28 days of first injection of CAWS to characterize the inflammatory profile and vascular function. Results: CAWS induced a severe vasculitis characterized by immune cells infiltration and high inflammatory markers in coronary arteries and abdominal aortae accompanied by vascular dysfunction, which was characterized by higher contractility to norepinephrine [(mN) Ctrl: 3.60 ± 0.3 n=4 vs. KD: 5.72 ± 0.2 n=4, *P<0.05]. Furthermore, significant increases in cardiac and vascular CCR5 expression and circulating CCL5 levels (main CCR5 ligand) were observed in KD group. Interestingly, CCR5-/- mice demonstrated an exacerbated vasculitis in coronary arteries and abdominal aortae and a worse vascular dysfunction [CCR5-/- KD (mN): 6.70 ± 0.4 n=5, *P<0.05 vs KD]. To study the mechanisms by which lack in CCR5 triggers an exaggerated vasculitis, we analyzed the circulating profile of cytokines and chemokines via proteome array. Multiple inflammatory cytokines (IL-1β IL-6, IL-17 and TNF-α) and chemokines (CXCL10, CXCL1, 2, 11, 12, 13, and 19, as well as 1, CCL2, 3, 4, 5, 11, and 12) were significantly elevated in KD group. Plasma samples from CCR5-/- KD revealed a further increase in several cytokines and chemokines, with an impressive increase in IL-6 increased [CCR5+/+-CAWS: 2.43 vs CCR5 -/- -CAWS: 38.0 n=5, *P<0.05 (Fold increases vs the respective controls)]. Conclusion: These data indicate that CCR5 operates as a holder for exaggerated vasculitis associated with KD likely via adjusting the formation and release of inflammatory cytokines such as IL-6. Our data helps unrevealing a possible mechanism by which polymorphism in CCR5 can increase the severity of vasculitis. Future studies are necessary to understand how CCR5 regulates cytokines formation.

NHLBI-R00 (R00HL14013903), AHA-CDA (CDA857268), Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania Vitalant, and Children's Hospital of Pittsburgh of the UPMC Health System.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.