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Non-receptor type, proline-rich protein tyrosine kinase 2 (Pyk2) is a possible therapeutic target for Kawasaki disease

机译:非受体类型,富含富含蛋白酪氨酸激酶2(Pyk2)是川崎病的可能治疗靶标

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摘要

Abstract Kawasaki disease (KD) is a paediatric vasculitis whose pathogenesis remains unclear. Based on experimental studies using a mouse model for KD, we report here that proline-rich protein tyrosine kinase 2 (Pyk2) plays a critical role in the onset of KD-like murine vasculitis. The mouse model for KD was prepared by administrating a Candida albicans water-soluble fraction (CAWS). Unlike CAWS-treated WT mice, CAWS-treated Pyk2-Knockout (Pyk2-KO) mice did not develop apparent vasculitis. A sustained increase in MIG/CXCL9 and IP-10/CXCL10, both of which have potent angiostatic activity, was observed in CAWS-treated Pyk2-KO mice. CAWS-induced activation of STAT3, which negatively regulates the expression of these chemokines, was also attenuated in macrophages derived from Pyk2-KO mice. The present study suggests that defects in Pyk2 suppress KD-like experimental vasculitis, presumably through CXCL9- and CXCL10-dependent interference with neo-angiogenesis. Since Pyk2-KO mice show no life-threatening phenotype, Pyk2 may be a promising therapeutic molecular target for KD. Highlights ? Pyk2 plays a crucial role in the onset of Kawasaki disease-like murine vasculitis. ? Pyk2 deficiency might attenuate neo-angiogenesis involved in developing vasculitis. ? Pyk2 could be a molecular target to treat Kawasaki disease.
机译:摘要川崎病(KD)是一种儿科血管炎,其发病机制仍然不清楚。基于使用小鼠模型的KD实验研究,我们在此报告富含脯氨酸的蛋白酪氨酸激酶2(PYK2)在KD样鼠血管炎的发作中起着关键作用。通过施用念珠菌白醛水溶性级分(CAWS)来制备KD的小鼠模型。与CAW治疗的WT小鼠不同,CAWS处理的Pyk2-kexptout(Pyk2-Ko)小鼠没有发展明显的血管炎。在Caws处理的Pyk2-Ko小鼠中观察到MIG / CXCL9和IP-10 / CXCL10的持续增加,两者都有有效的血管活性活性。 CAWS诱导的STAT3的激活,其负调节这些趋化因子的表达,也衰减于来自Pyk2-Ko小鼠的巨噬细胞中。本研究表明,Pyk2中的缺陷抑制了KD样的实验血管炎,可能是通过CXCL9和CXCL10依赖性干扰新血管生成的干扰。由于Pyk2-Ko小鼠没有威胁危及生命的表型,因此Pyk2可以是Kd的有希望的治疗分子靶标。强调 ? Pyk2在川崎病般的小鼠血管炎的发作中起着至关重要的作用。还Pyk2缺乏可能会衰减参与发展血管炎的新血管生成。还Pyk2可以是治疗川崎病的分子靶标。

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  • 作者单位

    Department of Pediatric Cardiology and Nephrology Graduate School of Medical Science Kyoto;

    Department of Pediatric Cardiology and Nephrology Graduate School of Medical Science Kyoto;

    Laboratory for Immunopharmacology of Microbial Products School of Pharmacy Tokyo University of;

    Department of Cardiovascular Medicine Graduate School of Medical Science Kyoto Prefectural;

    Laboratory for Immunopharmacology of Microbial Products School of Pharmacy Tokyo University of;

    Department of Pediatric Cardiology and Nephrology Graduate School of Medical Science Kyoto;

    Department of Pediatric Cardiology and Nephrology Graduate School of Medical Science Kyoto;

    Department of Pediatric Cardiology and Nephrology Graduate School of Medical Science Kyoto;

    Department of Pediatric Cardiology and Nephrology Graduate School of Medical Science Kyoto;

    Department of Pediatric Cardiology and Nephrology Graduate School of Medical Science Kyoto;

    Department of Pediatric Cardiology and Nephrology Graduate School of Medical Science Kyoto;

    Department of Pediatric Cardiology and Nephrology Graduate School of Medical Science Kyoto;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学免疫学;
  • 关键词

    Kawasaki disease; Vasculitis; Pyk2; IP-10;

    机译:川崎病;血管炎;PYK2;IP-10;

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