Adeno-associated Virus Vector-mediated Interleukin-10 Induction Prevents Vascular Inflammation in a Murine Model of Kawasaki Disease View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-05-15

AUTHORS

Jun Nakamura, Sachiko Watanabe, Hiroaki Kimura, Motoi Kobayashi, Tadayoshi Karasawa, Ryo Kamata, Fumitake Usui-Kawanishi, Ai Sadatomo, Hiroaki Mizukami, Noriko Nagi-Miura, Naohito Ohno, Tadashi Kasahara, Seiji Minota, Masafumi Takahashi

ABSTRACT

Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin-10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis. Mice were injected intramuscularly with adeno-associated virus (AAV) vector encoding IL-10, then treated with CAWS. The induction of AAV-mediated IL-10 (AAV-IL-10) significantly attenuated the vascular inflammation and fibrosis in the aortic root and coronary artery, resulting in the improvement of cardiac dysfunction and lethality. The predominant infiltrating inflammatory cells in the vascular walls were Dectin-2+CD11b+ macrophages. In vitro experiments revealed that granulocyte/macrophage colony-stimulating factor (GM-CSF) induced Dectin-2 expression in bone marrow-derived macrophages and enhanced the CAWS-induced production of tumor necrosis factor-α (TNF-α) and IL-6. IL-10 had no effect on the Dectin-2 expression but significantly inhibited the production of cytokines. IL-10 also inhibited CAWS-induced phosphorylation of ERK1/2, but not Syk. Furthermore, the induction of AAV-IL-10 prevented the expression of TNF-α and IL-6, but not GM-CSF and Dectin-2 at the early phase of CAWS-induced vasculitis. These findings demonstrate that AAV-IL-10 may have therapeutic application in the prevention of coronary vasculitis and aneurysm formation, and provide new insights into the mechanism underlying the pathogenesis of KD. More... »

PAGES

7601

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-25856-0

DOI

http://dx.doi.org/10.1038/s41598-018-25856-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1103911362

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29765083


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25 schema:description Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin-10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis. Mice were injected intramuscularly with adeno-associated virus (AAV) vector encoding IL-10, then treated with CAWS. The induction of AAV-mediated IL-10 (AAV-IL-10) significantly attenuated the vascular inflammation and fibrosis in the aortic root and coronary artery, resulting in the improvement of cardiac dysfunction and lethality. The predominant infiltrating inflammatory cells in the vascular walls were Dectin-2+CD11b+ macrophages. In vitro experiments revealed that granulocyte/macrophage colony-stimulating factor (GM-CSF) induced Dectin-2 expression in bone marrow-derived macrophages and enhanced the CAWS-induced production of tumor necrosis factor-α (TNF-α) and IL-6. IL-10 had no effect on the Dectin-2 expression but significantly inhibited the production of cytokines. IL-10 also inhibited CAWS-induced phosphorylation of ERK1/2, but not Syk. Furthermore, the induction of AAV-IL-10 prevented the expression of TNF-α and IL-6, but not GM-CSF and Dectin-2 at the early phase of CAWS-induced vasculitis. These findings demonstrate that AAV-IL-10 may have therapeutic application in the prevention of coronary vasculitis and aneurysm formation, and provide new insights into the mechanism underlying the pathogenesis of KD.
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31 schema:keywords AAV
32 Candida albicans water-soluble fraction
33 Dectin
34 Dectin-2 expression
35 ERK1/2
36 GM-CSF
37 IL-10
38 IL-10 supplementation
39 IL-6
40 Kawasaki disease
41 Syk
42 TNF
43 adeno
44 aneurysm formation
45 aortic root
46 applications
47 artery
48 bone marrow-derived macrophages
49 cardiac dysfunction
50 cardiac inflammation
51 cause
52 cells
53 certain number
54 colony-stimulating factor
55 coronary artery
56 coronary vasculitis
57 cytokines
58 disease
59 dysfunction
60 early phase
61 effect
62 experiments
63 expression
64 expression of TNF
65 factors
66 fibrosis
67 findings
68 formation
69 fraction
70 granulocyte/macrophage colony-stimulating factor
71 heart disease
72 immunoglobulin therapy
73 improvement
74 induction
75 inflammation
76 inflammatory cells
77 insights
78 interleukin-10
79 interleukin-10 induction
80 intravenous immunoglobulin therapy
81 lethality
82 macrophage colony-stimulating factor
83 macrophages
84 marrow-derived macrophages
85 mechanism
86 mice
87 model
88 murine model
89 necrosis factor
90 negative regulator
91 new insights
92 number
93 pathogenesis
94 pathogenesis of KD
95 patients
96 pediatric heart disease
97 phase
98 phosphorylation
99 phosphorylation of ERK1/2
100 prevention
101 production
102 production of cytokines
103 regulator
104 roots
105 subsequent aneurysm formation
106 supplementation
107 therapeutic applications
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109 tumor necrosis factor
110 vascular inflammation
111 vascular wall
112 vasculitis
113 vector
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115 wall
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