Augmented TLR2 expression on monocytes in both human Kawasaki disease and a mouse model of coronary arteritis.

I-Chun Lin,Hong-Ren Yu,Rong-Fu Chen,Ho-Chang Kuo,Lin Wang,Shun-Chen Huang,Chien-Fu Huang,Shao-Ju Chien,Feng-Shen Wang,Chih-Lu Wang,Ying-Jui Lin,Kuender D Yang,Markus M Heimesaat

doi:10.1371/journal.pone.0038635

Abstract

BackgroundKawasaki disease (KD) of unknown immunopathogenesis is an acute febrile systemic vasculitis and the leading cause of acquired heart diseases in childhood. To search for a better strategy for the prevention and treatment of KD, this study compared and validated human KD immunopathogenesis in a mouse model of Lactobacillus casei cell wall extract (LCWE)-induced coronary arteritis.MethodsRecruited subjects fulfilled the criteria of KD and were admitted for intravenous gamma globulin (IVIG) treatment at the Kaohsiung Chang Gung Memorial Hospital from 2001 to 2009. Blood samples from KD patients were collected before and after IVIG treatment, and cardiovascular abnormalities were examined by transthoracic echocardiography. Wild-type male BALB/c mice (4-week-old) were intraperitoneally injected with LCWE (1 mg/mL) to induce coronary arteritis. The induced immune response in mice was examined on days 1, 3, 7, and 14 post injections, and histopathology studies were performed on days 7 and 14.ResultsBoth 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, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (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.ConclusionThis result suggests that that 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.

Highlights

Kawasaki disease (KD) is a common cause of systemic vasculitis in young children, mostly affecting medium- and large-sized vessels
The results indicated that TLR2 surface expression on CD14+ monocytes significantly increased on days 3, 7 and 14 in Lactobacillus casei cell wall extract (LCWE)-treated mice compared to that in the control mice (P = 0.035, P = 0.004, P = 0.002, respectively) (Figure 4B)
The results of this study demonstrate the similar features of monocyte TLR2 augmentation, immune abnormalities and cardiovascular lesions in human KD patients and LCWE-treated mice

Summary

Introduction

Kawasaki disease (KD) is a common cause of systemic vasculitis in young children, mostly affecting medium- and large-sized vessels. Coronary arteritis/coronary artery lesions (CALs), such as coronary artery ectasia and aneurysms, are the major devastating abnormalities associated with KD [1,2]. KD with CALs is one of the leading causes of acquired heart diseases in childhood [3,4]. The current standard treatment with highdose intravenous gamma globulin (IVIG, 2 g/kg) lowers the incidence of CALs from 25% to approximately 5% in cases of transient coronary ectasia and to 1% in cases of giant coronary aneurysms [10,11]. Kawasaki disease (KD) of unknown immunopathogenesis is an acute febrile systemic vasculitis and the leading cause of acquired heart diseases in childhood. To search for a better strategy for the prevention and treatment of KD, this study compared and validated human KD immunopathogenesis in a mouse model of Lactobacillus casei cell wall extract (LCWE)-induced coronary arteritis

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