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Published on: March 7, 2022
CDCP1 on Dendritic Cells Contributes to the Development of a Model of Kawasaki Disease
Yu Lun1,2, Nozha Borjini1, Noriko N Miura3
1Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Insights
Cub domain-containing protein 1 (CDCP1) deficiency attenuated vasculitis in a mouse model of Kawasaki disease (KD). CDCP1 regulates IL-6 production in dendritic cells, suggesting a role in KD pathogenesis.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Kawasaki disease (KD) etiology and pathology are not fully understood.
- Cub domain-containing protein 1 (CDCP1) is linked to poor prognosis in solid tumors and upregulated in SARS-CoV-2-infected children with vasculitis.
- The role of CDCP1 in Kawasaki disease has not been previously investigated.
Purpose of the Study:
- To investigate the role of CDCP1 in the pathogenesis of Kawasaki disease.
- To explore the mechanism by which CDCP1 influences KD-related vasculitis.
Main Methods:
- Utilized a mouse model of Kawasaki disease induced by Candida albicans water-soluble fraction (CAWS) administration.
- Generated and analyzed CDCP1 knockout (KO) mice.
- Assessed serum cytokine and antibody levels, and evaluated coronary and aortic vasculitis.
- Investigated CDCP1 expression in immune cells, specifically dendritic cells (DCs), and its regulation by CAWS.
- Examined the Syk-MAPK signaling pathway in CDCP1 KO DCs.
Main Results:
- CDCP1 KO mice showed reduced coronary and aortic vasculitis compared to wild-type mice.
- Serum levels of CAWS-specific IgM/IgG2a and IL-6 were decreased in CDCP1 KO mice.
- CDCP1 was constitutively expressed on dendritic cells (DCs) and upregulated by CAWS.
- CAWS-induced IL-6 production was diminished in CDCP1 KO DCs, linked to impaired Syk-MAPK signaling.
Conclusions:
- CDCP1 plays a significant role in the development of Kawasaki disease vasculitis.
- CDCP1 modulates IL-6 production from dendritic cells via the Syk-MAPK signaling pathway.
- Targeting CDCP1 may offer a novel therapeutic strategy for Kawasaki disease.
Abstract:
The etiology and pathology of Kawasaki disease (KD) remain elusive. Cub domain-containing protein 1 (CDCP1), a cell-surface protein that confers poor prognosis of patients with certain solid tumors, was recently identified as one of the most significantly upregulated genes in SARS-CoV-2-infected children who developed systemic vasculitis, a hallmark of KD. However, a potential role of CDCP1 in KD has not previously been explored. In this study, we found that CDCP1 knockout (KO) mice exhibited attenuated coronary and aortic vasculitis and decreased serum Candida albicans water-soluble fraction (CAWS)-specific IgM/IgG2a and IL-6 concentrations compared with wild-type mice in an established model of KD induced by CAWS administration. CDCP1 expression was not detectable in cardiomyocytes, cardio fibroblasts, or coronary endothelium, but constitutive expression of CDCP1 was observed on dendritic cells (DCs) and was upregulated by CAWS stimulation. CAWS-induced IL-6 production was significantly reduced in CDCP1 KO DCs, in association with impaired Syk-MAPK signaling pathway activation. These novel findings suggest that CDCP1 might regulate KD development by modulating IL-6 production from DCs via the Syk-MAPK signaling pathway.
