Protective role of complement signaling in Kawasaki disease vasculitis
Asli E. Atici, Begüm Kocatürk, Benjamin L. Ross, Emily A. Aubuchon, Rebecca A. Porritt, Thacyana T. Carvalho, Takahiro Namba, Youngho Lee, Magali Noval Rivas, Moshe Arditi
Asli E. Atici, Begüm Kocatürk, Benjamin L. Ross, Emily A. Aubuchon, Rebecca A. Porritt, Thacyana T. Carvalho, Takahiro Namba, Youngho Lee, Magali Noval Rivas, Moshe Arditi
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Research Article Immunology Inflammation Vascular biology

Protective role of complement signaling in Kawasaki disease vasculitis

Abstract

Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown etiology and the leading cause of acquired heart disease among children. Complement activation has long been observed in patients with acute KD; however, its contribution to disease development remains unknown. Here, using publicly available datasets, we showed that patients with acute KD exhibited higher expression of complement products in whole blood, consistent with the activation of the complement pathway. Similarly, in the Lactobacillus casei cell wall extract (LCWE) murine model of KD, LCWE injection induced increased expression of complement products in cardiovascular tissues, suggestive of activation of the complement pathways. C3-deficient mice or WT mice treated with the complement C5a receptor 1 (C5ar1) antagonist developed significantly more severe LCWE-induced cardiovascular lesions and vasculitis. Furthermore, we observed that LCWE binds to serum C3, an opsonizing factor that labels microbial targets for clearance, and LCWE deposition in the liver was significantly higher in C3-deficient mice compared with WT mice. Overall, our data indicate that blocking the complement system significantly exacerbates LCWE-induced KD vasculitis, likely by impairing C3-mediated clearance of LCWE. These data suggest that the complement pathway may play a protective role in KD pathogenesis by promoting clearance of a potential bacterial or viral trigger of KD.

Authors

Asli E. Atici, Begüm Kocatürk, Benjamin L. Ross, Emily A. Aubuchon, Rebecca A. Porritt, Thacyana T. Carvalho, Takahiro Namba, Youngho Lee, Magali Noval Rivas, Moshe Arditi

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Figure 5

C3 deficiency or C5a receptor blockade exacerbates murine KD vasculitis.

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C3 deficiency or C5a receptor blockade exacerbates murine KD vasculitis....
(A) C3b and C5a levels in the peritoneal lavage of WT mice injected with PBS or LCWE for 6 or 24 hours (n = 5–7/group). (B) Representative H&E-stained heart sections and heart vessel inflammation scores of LCWE-injected WT and C3–/– mice at 2 weeks after injection (n = 15–18/group). Scale bars: 500 μm. (C) Representative pictures of the abdominal aorta areas and maximal abdominal aorta diameter measurements of LCWE-injected WT and C3–/– mice at 2 weeks after injection (n = 15–18/group). (D) IL-1β measurements in the peritoneal lavage of WT and C3–/– mice injected with PBS or LCWE 24 hours after injection (n = 4, 5/group). (E) Representative images and quantification of FLICA (green), F4/80 (red), and NLRP3 (purple) staining in hearts from LCWE-injected WT and C3–/– mice at 2 weeks after injection (n = 5/group). DAPI (blue) was used to stain nuclei. Yellow arrows indicate triple positive cells. Scale bars: 50 μm. (F) Representative H&E-stained heart sections and heart vessel inflammation scores of LCWE-injected WT mice treated with vehicle or PMX205 (C5ar1 antagonist) at 2 weeks after injection (n = 11–14/group). Scale bars: 500 μm. (G) Representative pictures of the abdominal aorta areas and maximal abdominal aorta diameter measurements of LCWE-injected WT mice treated with vehicle or PMX205 at 2 weeks after injection (n = 11–14/group). Data are pooled from 2 separate experiments in B, C, F, and G. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.001 by 1-way ANOVA with Tukey’s (A) and unpaired 2-tailed t test (B–G).