| Summary: | 博士 === 長庚大學 === 臨床醫學研究所 === 100 === Kawasaki disease (KD) is the leading cause of acquired heart disease in children worldwide. Cumulating evidences suggest that coronary arterial lesions (CALs) in childhood serve as one of the important risk factors contributory to acute coronary syndrome in young adulthood. Of unknown underlying mechanism, both innate and adaptive immune responses are involved in the pathogenesis of such CALs. Due to extremely scarce of human cardiac specimen from KD patients, Lactobacillus casei cell wall extract (LCWE) was used to induce mice to develop CALs mimicry to those in human KD patients. In this study, innate immune response both in the peripheral blood and the murine model of toll-like receptor (TLR)-2 and dectin-1/spleen tyrosine kinase (Syk) pathway of macrophages were studied both in vitro and in vivo. The participation of adaptive immune responses and T cell differentiation were also examined in this LCWE-induced CAL mouse model. In an attempt to validate this animal model in the translation research, the immune responses and cardiovascular abnormalities were compared between human KD patients and LCWE-induced CAL mice.
Results showed that LCWE induced in vitro macrophage activation with increased production of interleukin (IL)-6, tumor necrosis factor (TNF)-a, and monocyte chemoattractant protein (MCP)-1, concomitantly with Syk activation, and dectin-1 and TLR2 enhancement. In vivo, LCWE induced infiltration of dectin-1+ macrophages into CALs, which correlated to cardiac upregulation of IL-6 on day 14 post-injection. Meanwhile, LCWE-treated mice exhibited increases in plasma levels of interferon (IFN)-γ, IL-2, IL-4, IL-17A, IL-10, and IL-12p70 on day 3 post-injection and higher percentage of CD4+/IFN-γ+, and CD4+/IL-17A+ splenocytes on day 14 post-injection. In LCWE-induced CALs, infiltration of CD4+ and CD8+ cells around aortic roots were associated with up-regulation of IFN-γ and IL-17A mRNA production. Most importantly, Syk inhibition alleviated LCWE-induced arteritis in BALB/c mice, associated with significantly suppressed LCWE-induced IL-6, MCP-1, as well as IFN-γ, IL-2, IL-4, IL-17A, IL-10, and IL-12p70. Moreover, both human KD patients and LCWE-treated mice developed coronary arteritis, myocarditis, valvulitis, and pericarditis, as well as elevated plasma levels of interleukin IL-2, IL-6, IL-10, MCP-1, and TNF-α in acute phase. Most of these proinflammatory cytokines declined to normal levels in mice, whereas normal levels were achieved in patients only after IVIG treatment, with a few exceptions. Toll-like receptor (TLR)-2, but not TLR4 surface enhancement on circulating CD14+ monocytes, was augmented in KD patients before IVIG treatment and in LCWE-treated mice, which declined in patients after IVIG treatment.
This study demonstrates that the macrophage dectin-1/Syk-mediated pathway is involved in LCWE-induced CALs and production of IL-6 and MCP-1, and also characterizes Th1/Th2/Treg/Th17 paradigm regarding CD4+ T cell differentiation in this model. Such importance of dectin-1/Syk pathway in the development of murine CALs warrants further investigation specifically on their role in monocyte/macrophage activation and T cell receptor signaling, as well as even further implication in human KD. Meanwhile, not only TLR2 augmentation on CD14+ monocytes might be an inflammatory marker for both human KD patients and LCWE-induced CAL mouse model but also this model is feasible for studying therapeutic strategies of coronary arteritis in human KD by modulating TLR2-mediated immune activation on CD14+ monocytes. It would be great of value to provide such fundamental evidences, supporting future research and development in therapeutic strategies to this chronic vascular remodeling of CALs in human KD patients.
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