Galectin-9在病毒性心肌炎发病中的作用及其机制
摘要
病毒性心肌炎(viral myocarditis, VMC)是一临床常见心血管系统疾病。早在1899年Fiedler KL就曾报道过3例现代概念的VMC,此后,欧美各国VMC的临床及尸检报道日益增多。20世纪70年代后,中国及日本等亚洲国家相继报道了VMC的发生,近年来尤其在我国,VMC的发病逐年上升,VMC已成为青少年不明原因猝死的主要原因之一。不仅如此,慢性VMC常可导致扩张性心脏病的发生,在美国每年新增扩张性心脏病病人多达100,000人,已成为心脏移植手术的重要原因之一。VMC严重危害生命健康,然而迄今为止,VMC的治疗尚无有效的办法,其根本原因在于VMC的发病机制还不完全清楚,因此,阐明VMC的发病机制具有重要的理论和实践意义。
目前认为,VMC的发生是一个多因素参与的复杂的过程,病毒感染是VMC重要的病因之一。肠道病毒、巨细胞病毒、腺病毒、流感病毒、肝炎病毒等病毒感染都可以诱发VMC。其中肠道病毒尤其是柯萨奇病毒感染是最常见病因。B3型柯萨奇病毒(coxsackievirus group B type 3, CVB3),微小无衣壳正链RNA病毒,属于小核糖核酸病毒科。早在20世纪50年代,B3型柯萨奇病毒已被发现能累及心肌,导致VMC。流行病学调查中发现,CVB3感染在不同性别人群中发病率和严重程度明显不同,VMC在男性人群中多发,症状也较为严重,并易发展为慢性心肌炎和扩张性心肌病。与人类相似,CVB3感染的雌性和雄性BALB/c小鼠也显示不同严重程度的心肌炎。尽管CVB3感染的发病机制已经研究了很多年,但直到近来才发现多种机制参与了CVB3诱导的VMC的发生、发展和进程。
CD4+T细胞的免疫偏移可以影响VMC严重性。一方面,Thl型免疫应答被认为是引起心肌组织损伤的主要原因：有研究发现,CD4基因敲除小鼠中CVB3诱导的VMC可以得到有效的缓解,证实了CD4+T细胞在VMC中的作用；Huber等也发现CD4+Thl细胞应答对于CVB3诱导的VMC是必需的。另一方面,CD4+调节性T细胞(regulatory T cells, Tregs)可以降低心肌炎症,缓解心肌炎的发病：Ono等发现,高表达GITR的Foxp3+ Tregs可以控制自身免疫性心肌炎；Huber等证实CVB3病毒突变体可以通过诱导和维持Tregs的数量,有效的缓解心肌炎。
炎性细胞因子在VMC的发病过程中也发挥重要作用。在易感小鼠中,心肌组织中IL-1β和IL-18水平的增加直接与疾病的严重性呈正相关；在非易感小鼠中,IL-1或TNF-α却能促进心肌炎的发病。本室前期研究发现,外源性注射IL-4可以显著改善CVB3感染小鼠的心肌炎症和心肌炎的严重程度。因此,治疗CVB3诱导的VMC理想的方法就是促进细胞因子向抗炎因子转化,同时诱导或扩增抑制性细胞(?)CD4+ Tregs。
Galectin-9,β半乳糖苷结合凝集素家族成员,可诱导嗜酸性粒细胞、肿瘤细胞和T细胞凋亡。通过Ca2+ -caspasel信号途径,galectin-9(?)(?)优先诱导活化CD4+T细胞发生凋亡。T细胞免疫球蛋白域和粘蛋白域蛋白-3(T-cell immunoglobulin domain and mucin domain protein-3, Tim-3), galectin-9的受体,选择性表达于终末分化Th1细胞,在Th17、Tregs表面也有一定的表达。Galectin-9在体内外均可以诱导Tim-3表达的细胞发生凋亡。有研究发现,galectin-9治疗可以有效的缓解实验性变态反应性脑炎,一种中枢神经系统脑炎。而且,在胶原诱导的关节炎动物模型以及HSV诱导的损伤模型中,galectin-9通过调节T细胞应答,如抑制Th17的产生,同时促进Tregs的分化和扩增,从而达到治疗疾病的目的。
在本研究中,我们用CVB3感染的雄性BALB/c小鼠,观察CVB3感染后心肌中galectin-9的表达变化,结果显示CVB3感染后雄性BALB/c小鼠心肌galectin-9的表达显著升高。进一步研究发现galectin-9可以促进Tregs的富集,并有效的缓解CVB3诱导的VMC。那么galectin-9是通过什么机制缓解VMC的发作?是影响病毒复制还是通过调节细胞免疫应答?Galectin-9促进Tregs富集的机制又是什么?因此,在本研究中我们利用CVB3感染的VMC模型,探讨了galectin-9在VMC发病中的作用及相关机制。
第一部分Galectin-9在病毒性心肌炎发病中的作用
一、CVB3感染前后galectin-9的表达变化
Galectins属于β半乳糖苷结合凝集素家族。现有的研究表明,galectins在各种生理或病理过程中发挥重要作用,如免疫炎症反应、肿瘤、动脉粥样硬化和糖尿病等。其中galectin-1,-3,-9在调节免疫应答和炎症反应中发挥重要作用。
为了研究galectins在CVB3诱导的VMC中的作用,我们首先观察了CVB3感染前后小鼠心肌中galectin-1,-3,-9的表达变化,结果发现CVB3感染可以显著上调小鼠心肌galectin-1,-9 mRNA的表达。由于galectin-1在病毒感染中研究较为清楚,我们进一步关注了CVB3感染前后galectin-9在不同组织中的表达变化,发现CVB3感染后,小鼠心肌、脾脏和肠系膜淋巴结中galectin-9 mRNA的表达显著升高。免疫组化结果也显示CVB3感染增加了小鼠心肌中galectin-9蛋白的表达。
上述结果提示,galectin-9可能参与了CVB3诱导的VMC的发病。
二、Galectin-9治疗前后BALB/c小鼠病毒性心肌炎严重程度的差异
VMC以心肌间质炎性细胞浸润为特征,导致心肌细胞灶性坏死,纤维化,最终导致心脏功能丧失。以CVB3感染小鼠建立心肌炎动物模型,很好地模拟了临床上VMC疾病过程。VMC的判断指标主要有体重减轻、血清学、病理学以及死亡率等。用galectin-9蛋白腹腔注射治疗CVB3感染雄性BALB/c小鼠,结果发现两组小鼠在感染后第3天体重都开始下降,其中未治疗组(PBS组)小鼠体重持续下降,至第7天体重减轻率达15%,而galectin-9治疗组BALB/c小鼠感染后第5天体重开始恢复,随后体重逐渐增加。从血清学指标来看,在感染后第7天,未治疗组BALB/c小鼠血清CK、CK-MB的活性显著升高,cTnI水平也明显升高；而galectin-9治疗组小鼠血清CK、CK-MB的活性和cTnI水平显著低于未治疗组小鼠。心脏组织HE染色显示未治疗组BALB/c小鼠心脏显示片状的炎性细胞浸润和心肌细胞坏死,而galectin-9治疗组小鼠心脏仅有少量炎性细胞浸润；治疗组小鼠心肌炎的炎症面积远小于未治疗组,而且治疗组小鼠心脏浸润CD45+单个核细胞比例显著降低。最后,从死亡率来看,至感染第10天,未治疗组BALB/c小鼠的死亡率高达70%,而galectin-9治疗组小鼠的死亡率仅为15%。综合上述各项指标可以看出,galectin-9治疗可以显著缓解CVB3诱导的VMC。
三、Galectin-9治疗对CVB3感染小鼠炎症性细胞因子分泌的影响
炎症性细胞因子如TNF-α、IFN-γ、IL-4和IL-10等在心肌炎的发病过程中发挥重要作用。因此,我们检测了galectin-9治疗对小鼠心脏局部和血清中炎性细胞因子TNF-α、IFN-γ、IL-4和IL-10分泌的影响,发现galectin-9治疗可以显著下调促炎性细胞因子TNF-a和IFN-y的分泌,同时促进抗炎性细胞因子IL-4和IL-10的分泌。
以上结果显示,galectin-9可以有效的缓解CVB3诱导的VMC,并促进细胞因子微环境向抗炎性转化,证实galectin-9的确参与了VMC的发病。
第二部分Galectin-9在病毒性心肌炎中的作用机制探讨
一、Galectin-9对病毒复制的影响
CVB3感染心肌细胞是诱发VMC的前提条件。由此我们必须排除一个可能即galectin-9缓解CVB3诱导的VMC是由于降低心肌病毒复制造成的。因此我们首先检测了galectin-9治疗前后CVB3感染的BALB/c小鼠心脏组织中CVB3病毒RNA数量和病毒滴度的变化,结果发现galectin-9并没有引起心脏组织中CVB3病毒RNA数量和病毒滴度的改变。
二、Galectin-9对细胞免疫应答的影响
由于galectin-9缓解VMC并没有降低心肌病毒复制,我们进一步探讨了galectin-9治疗对细胞免疫应答的影响。结果显示CVB3感染过程中,galectin-9可以显著降低小鼠心脏和脾脏中CD4+T细胞的比例,同时增加Tregs、CD11b+及Gr-1+细胞的数量。由于Tim-3 (galectin-9特异性受体)和TLR4的相互作用在VMC的发病过程中发挥重要作用,我们还检测了galectin-9对Tim-3和TLR4在免疫细胞表面表达的影响,发现galectin-9降低了CD4+T细胞Tim-3的表达,但其在巨噬细胞表面的表达显著升高；同时galectin-9显著降低了TLR4在CDllb+细胞及巨噬细胞表面的表达。
上述结果提示,galectin-9缓解CVB3诱导的VMC并不是直接降低病毒复制,而是通过调节细胞免疫应答参与心肌炎的发病,Tregs和CD11b+细胞可能参与其中。
前面的实验结果显示,galectin-9可以有效的缓解CVB3诱导的VMC,我们进一步探讨了其可能的细胞学机制以及是否这种作用依赖于效应T细胞数量的降低和Tregs数量的升高。
三、Galectin-9对于CD4+T细胞凋亡和增殖的影响
现有的研究表明,galectin-9可以优先诱导效应CD4+T细胞的凋亡,而在CVB3诱导的VMC模型中,分泌IFN-γ的CD4+T cells是影响疾病严重性的重要因素。因此,我们首先检测了galectin-9对CD4+T细胞凋亡的影响,发现galectin-9可以显著促进CD4+T细胞发生凋亡。进一步研究发现,galectin-9主要诱导CD4+CD2low/int效应T细胞凋亡(>90%),而对于CD4+CD25high Tregs的促凋亡作用甚微(<10%)。我们同时也检测了galectin-9对CD4+ T细胞增殖的影响,发现galectin-9能抑制CD4+T细胞增殖,并主要抑制CD4+CD25low/int效应T细胞的增殖,而并不影响CD4+CD25high Tregs的增殖。Galectin-9差异调节Tregs和效应T细胞凋亡和增殖可能是由于其受体Tim-3的表达差异造成的,相关机制仍需进一步研究。
四、Galectin-9在诱导调节性T细胞分化中的作用
Tregs在CVB3诱导的VMC的发病过程中发挥重要作用。为了探讨galectin-9是否影响Tregs应答,我们检测了galectin-9对Tregs分化的影响,发现galectin-9能促进CVB3感染的裸鼠心脏和脾脏中CD4+CD25-T细胞向Tregs转化。
五、Galectin-9在扩增CDllb+ Gr-1+细胞中的作用
前面的实验结果发现,galectin-9能显著增加CD11b+和Gr-1+细胞的比例,而CD11b和Gr-1是髓系来源抑制细胞(myeloid suppressor cells,MSCs)的特有表型,于是我们检测了galectin-9在调节CDl lb+Gr-1+细胞扩增中的作用,结果显示galectin-9能显著扩增CD11b+Gr-1+细胞。通过分析这群细胞的表型和细胞因子分泌情况,我们发现其具有髓系来源抑制细胞的表型。
许多研究表明,髓系来源抑制细胞可以促进Tregs的扩增。因此,我们接着研究了CD11b+Gr-1+细胞在扩增Tregs中的作用,结果显示,CD11b+Gr-1+细胞可以促进CD4+T细胞中Tregs的扩增,这种作用部分依赖于IL-10,而不依赖于TGF-β。
综上所述,本研究首次阐明了galectin-9在CVB3诱发的VMC发病中的作用；证实了galectin-9是通过调节细胞免疫应答参与了VMC的发病,并未影响病毒复制；多种机制参与了galectin-9对VMC的调节：Galectin-9差异调节效应T细胞和Tregs增殖和凋亡；CD11b+Gr-1+细胞的积累和Tregs的分化。本研究在一定程度上阐明VMC的发病机制,同时也为临床提供了一个有效的治疗靶点和理论支持。
The incidence and severity of heart disease, including myocarditis, is higher among men than women. Viral myocarditis (VMC), or inflammation of the heart, is a principal cause of heart failure in young adults often leading to chronic heart disease and dilated cardiomyopathy (DCM). Viral infection is one of the important reasons for VMC. Among the viruses, Coxsackievirus group B type 3 (CVB3) infection accounts for more than half of VMC cases. CVB3 is a member of the picomavirus family of small, non-enveloped, positive sense, RNA viruses, and are major etiological agents in clinical viral myocarditis. A murine model of CVB3 induced myocarditis has been established which mimicks many of the characteristics of the clinical disease. Although the pathogenesis of CVB3 infection has been studied for decades, it is only recently recognized that many variables, including viral genome structure, host genetic background, the age, and the immune status of the host, interact with each other to determine the initiation, occurrence and progression of viral myocarditis.
The bias of CD4+ Th immune response appears to influence the severity of myocarditis. On the one hand, the Thl immune response, rather than the Th2 immune response, is considered to be detrimental to heart tissue. Opavsky et al. found that the severity of disease is attenuated in CD4 knockout mice, confirming the role of CD4+ T cells in CVB3 induced myocarditis. Huber et al. found CD4+Thl cell responses are essential to CVB3 induced myocarditis susceptibility. On the other hand, regulatory T cells play a major role in protection against inflammation in the heart, and their alteration by viral infection may contribute substantially to the outcome of myocarditis. Recent studies have shown that autoimmune myocarditis and multiorgan inflammation are controlled by Foxp3+ T cells highly expressing the glucocorticoid-induced TNF receptor familyrelated protein (GITR). Depletion of the GITR+ T regulatory cells allowed activation of autoimmune heart disease. Huber and colleagues described myocarditis could be overcome by a coxsackievirus variant which maintained and induced regulatory T cells function.
Furthermore, cytokines play a key role in CVB3 induced myocarditis. In susceptible mice IL-1βand IL-18 play a significant role in the pathogenesis of CVB3 induced myocarditis. IL-1 or TNF-a can promote myocarditis in resistant B10.A mice. Our previous study indicated that exogenous administration of IL-4 is found to improve myocardial inflammation and the severity of myocarditis in mice infected with CVB3. Thus, therapeutic strategies of CVB3 induced myocarditis should consider regulation of regulatory T cells (Tregs) differentiation as well as inhibition of pro-inflammatory cells and Thl cytokines.
To shift the cytokine balance to anti-inflammatory cytokines and to delete pro-inflammatory Thl cells that closely associate with etiology of CVB3 induced myocarditis, it is necessary to discover novel biological substances that can selectively suppress the function or delete activated Thl cells, at the same time expanding Tregs. Galectin-9, one of the (3-galactoside binding animal lectins belonging to the galectin family, induces apoptosis of eosinophils, cancer cells, and T cells. Galectin-9 preferentially induces apoptosis of activated CD4+ T cells through Ca+ influx-calpain-caspasel pathway. Zhu et al. have recently demonstrated that galectin-9 is a ligand of T cell immunoglobulin- and mucin domain-containing molecule3 (TIM-3) that was expressed selectively on terminally differentiated Thl cells, Th17, Tregs, and that galectin-9 induces apoptosis of TIM-3-expressing cells in vitro and in vivo. Furthermore, exogenous administration of galectin-9 ameliorates experimental allergic encephalitis, an autoimmune disease of the central nervous system. More recently it has been shown that galectin-9 ameliorates a mouse collagen-induced arthritis (CIA) model and HSV induced lesions by suppressing the generation of Th17, promoting the induction of regulatory T cells.
In this study, we compared galectin-9 expression in different organs of males before and after CVB3 infection. Then we examined the effects of in vivo treatment with recombinant galectin-9 on the development of myocardial inflammation in male mice infected with CVB3. Meanwhile, we analyzed the modulation of immune cells in the heart and spleen of CVB3 infected male mice in vivo with or without recombinant galectin-9 treatment and explored the mechanisms involved.
The purpose of the present study was to clarify the role of galectin-9 in the development of murine acute myocarditis induced by CVB3 and its possible mechanisms involved.
1. Change of galectin-9 expression before and after CVB3 infection
Galectins are a family of animal lectins that bindβ-galactosides. Current research indicates that galectins play important roles in diverse physiological and pathological processes, including immune and inflammatory responses, tumour development and progression, neural degeneration, atherosclerosis, diabetes. Among these, galectin-1,-3,-9 are the key regulators of immune response and inflammation. To better understand the mechanisms responsible for increased heart disease in male mice, we first compared galectins expression in the heart from male BALB/c mice before and after CVB3 infection. We found galectin-9 mRNA expression as well as galectin-1 in the heart from males was up-regulated after CVB3 infection. Then we further focused on galectin-9 mRNA expression in different organs, and found it was significantly higher in the heart as well as spleen and mesenteric lymph node (MLN) after CVB3 infection by RT-PCR assessment. Subsequently we confirmed the higher expression of galectin-9 protein in the heart by immunohistochemistry after CVB3 infection.
2. Differential severity of CVB3 induced myocarditis before and after galectin-9 treatment
Viral myocarditis is characterized by inflammatory cells infiltration in the interstitial tissue of myocardium with the result of myocyte focal necrosis or fibrosis and finally the loss of heart function. It well mimics the characteristics of clinical viral myocarditis using CVB3 infected myocarditis murine model with the indices of serology, pathology and body weight reduced rate as well as mortality. From day 3 post-infection, the body weight of PBS treated mice decreased obviously. On day 7 post-infection, the body weight decreased 15%. While in galectin-9 treated mice, on day 3 post-infection, the body weight also reduced but then recovered on day 5. The activity of serum Creatine Kinase (CK) and MB isoenzyme of Creatine Kinase (CK-MB) was significantly down-regulated and the level of Cardiac Troponin I (cTnl) was also decreased in galectin-9 treated BALB/c mice on day 7 post-infection. The pathological studies, the most direct and important diagnosis criteria revealed that in PBS treated mice, on day 7 post-infection, H.E showed the focal infiltration of inflammatory cells and the massive necrosis of myocytes. While in galectin-9 treated mice, there was no obvious inflammatory cells infiltration and no myocyte necrosis. Moreover, lower frequency of CD45+ immune cells in the heart of galectin-9 treated mice than PBS treated mice confirmed the above histological findings. As far as mortality was concerned, the mortality in CVB3 infected male mice was 70%, which was much higher than that in galectin-9 treated mice with the mortality of 15%. From the above results, the conclusion could be drawn that galectin-9 alleviated the severity of viral myocarditis after CVB3 infection.
3. Effects of galectin-9 treatment on inflammatory cytokines production
Inflammatory cytokines, such as TNF-α, IFN-γ, IL-4 and IL-10 play a role in the initiation of inflammatory cell infiltration in the lesions. To clarify whether galectin-9 treatment regulates cytokines production, levels of inflammatory cytokines (TNF-α, IFN-γ, IL-4, IL-10) in myocardial tissue and serum from CVB3 infected mice were assessed with or without galectin-9 administration. CVB3 infection resulted in the increased levels of TNF-αand IFN-γin the mice. Galectin-9 treatment led to significant decreased levels of TNF-αand IFN-γin both myocardial tissue and serum of the infected mice, whereas galectin-9 increased the levels of IL-4 and IL-10. PartⅡPossible mechanisms underlies galectin-9 functions
1. Effects of galectin-9 treatment on CVB3 replication
CVB3 can infect myocytes and replicate in cells, which is the prerequisite to induce VMC. To exclude the possibility that galectin-9 could effectively rescue mice from lethal myocarditis was due to decreased CVB3 replication, the viral load in heart tissues was also assessed by real-time PCR and plaque assay, and it was found that galectin-9 treatment does not significantly change myocardial viral burden, suggesting that the alleviation of viral myocarditis by galectin-9 is not due to the direct down-regulation of viral replication.
2. Effects of galectin-9 treatment on immune response
Since alleviated inflammation in galectin-9 treated mice was not due to decreased viral replication in the heart, we next performed experiments to clarify whether galectin-9 modulates the balance of T immune response and influences the number of Tregs. Results showed that galectin-9 administration had significantly decreased percentage of CD4+ T cells, whereas it had remarkably increased percentage of Tregs as well as CDllb+ or Gr-1+ cells in heart and spleen from CVB3 infected mice. We further compared the level of Tim-3 (T cell Ig and mucin-3, the receptor of galectin-9) and TLR4 on immune cells isolated from the heart of males with or without galectin-9 treatment. Tim-3 expression was significantly reduced on CD4+ T cells but increased on macrophages from heart of males on day 7 p.i., while TLR4 expression was significantly reduced on CDllb+ cells and macrophages.
Since administration of galectin-9 alleviated CVB3 induced myocarditis, we addressed to analyze cellular mechanisms and whether the effects are entirely due to loss of pathogenic T cells and increased Tregs.
3. Influence of galectin-9 treatment on the apoptosis and proliferation of CD4+ T cells
Prior in vitro studies have indicated that galectin-9 triggering of pro-inflammatory CD4+ T cells causes them to undergo apoptosis. In the model of CVB3 induced myocarditis, since inflammation appeared to be mainly orchestrated by IFN-y producing CD4+ T cells, so we detected the effects of galectin-9 on the induction of apoptosis of CD4+ T cells. As shown in results, about 50% CD4+ T cells underwent apoptosis after galectin-9 treatment, perhaps accounting in part for the anti-inflammatory effect of galectin-9. Furthermore, while about 90% of CD4+CD25low/int effector T cells underwent apoptosis,10% of CD4+CD25high regulatory T cells were annexin V+
We further explored whether in vivo galectin-9 treatment would influence the proliferation of CD4+ T cells. As shown, BrdU+ proliferating CD4+ T cells increased in heart on day 7 after CVB3 infection, whereas it significantly decreased in mice receiving galectin-9 treatment. The decreased proliferative response mainly existed in the CD4+CD25low/int effector T cells.
These results indicated that in vivo galectin-9 administration efficiently down-regulated CD4+ T cell responses. The differential regulation of apoptosis and proliferation of effctor and regulatory T cells by galectin-9 maybe due to the differential expression of Tim-3.
4. Effects of galectin-9 treatment on the differentiation of regulatory T cells
In prior experiments have established that the severity of CVB3 induced myocarditis can be modulated by regulatory T cells. To determine whether galectin-9 administration to CVB3 infected mice had any influence on the Tregs response, experiments were done to clarify whether galectin-9 is involved in the differentiation of CD4+CD25+Foxp3+ Tregs. Thus, we transferred naive CD4+CD25-T cells into CVB3 infected nude mice on day 3 post-infection and galectin-9 was i.p. injected everyday till day 7. These mice were sacrificed on day 7 post-infection and heart infiltrated cells and splenocytes were separated, then the percentage of CD4+CD25+ Foxp3+ Tregs was determined by FACS. Results showed that there was a significant increase of CD4+ CD25+ Foxp3+ Tregs in the heart from galectin-9 treated mice compared to non-treated mice. In addition, the percentage of CD4+CD25+Foxp3+ Tregs in spleen from galectin-9 treated mice was significantly higher than non-treated mice. From the data described above, we clarified that galectin-9 promoted the induction of Tregs during CVB3 induced myocarditis in vivo.
5. Influence of galectin-9 treatment on expansion of myeloid suppressor cells
Galectin-9 treated animals, as compared with control animals, showed significantly expanded populations of CDllb+ and Gr-1+ cells, which phenotypes possessed by myeloid suppressor cells. So we detected the influence of galectin-9 treatment on expansion of CDllb+Gr-l+ cells. We found that galectin-9 promoted the expansion of CDllb+Gr-1+ cells, which expressed low level of F4/80, CD80,CD86 and IAd, a phenotypes possessed by myeloid suppressor cells. They also could secret IL-10 and TGF-β. Moreover, CDllb+Gr-1+ cells increased the number of regulatory T cells by expansion of previously existed cells, which partly depended on IL-10 production.
In conclusion, the present study demonstrated that galectin-9 may play a crucial role in CVB3 induced myocarditis and it may be one of the novel therapeutic candidates that can suppress autoimmune inflammation by regulating the T cell differentiation and the balance of pathogenic and regulatory T cells, such that pro-inflammatory cytokines production are inhibited and anti-inflammatory cytokines are enhanced.
目前认为,VMC的发生是一个多因素参与的复杂的过程,病毒感染是VMC重要的病因之一。肠道病毒、巨细胞病毒、腺病毒、流感病毒、肝炎病毒等病毒感染都可以诱发VMC。其中肠道病毒尤其是柯萨奇病毒感染是最常见病因。B3型柯萨奇病毒(coxsackievirus group B type 3, CVB3),微小无衣壳正链RNA病毒,属于小核糖核酸病毒科。早在20世纪50年代,B3型柯萨奇病毒已被发现能累及心肌,导致VMC。流行病学调查中发现,CVB3感染在不同性别人群中发病率和严重程度明显不同,VMC在男性人群中多发,症状也较为严重,并易发展为慢性心肌炎和扩张性心肌病。与人类相似,CVB3感染的雌性和雄性BALB/c小鼠也显示不同严重程度的心肌炎。尽管CVB3感染的发病机制已经研究了很多年,但直到近来才发现多种机制参与了CVB3诱导的VMC的发生、发展和进程。
CD4+T细胞的免疫偏移可以影响VMC严重性。一方面,Thl型免疫应答被认为是引起心肌组织损伤的主要原因：有研究发现,CD4基因敲除小鼠中CVB3诱导的VMC可以得到有效的缓解,证实了CD4+T细胞在VMC中的作用；Huber等也发现CD4+Thl细胞应答对于CVB3诱导的VMC是必需的。另一方面,CD4+调节性T细胞(regulatory T cells, Tregs)可以降低心肌炎症,缓解心肌炎的发病：Ono等发现,高表达GITR的Foxp3+ Tregs可以控制自身免疫性心肌炎；Huber等证实CVB3病毒突变体可以通过诱导和维持Tregs的数量,有效的缓解心肌炎。
炎性细胞因子在VMC的发病过程中也发挥重要作用。在易感小鼠中,心肌组织中IL-1β和IL-18水平的增加直接与疾病的严重性呈正相关；在非易感小鼠中,IL-1或TNF-α却能促进心肌炎的发病。本室前期研究发现,外源性注射IL-4可以显著改善CVB3感染小鼠的心肌炎症和心肌炎的严重程度。因此,治疗CVB3诱导的VMC理想的方法就是促进细胞因子向抗炎因子转化,同时诱导或扩增抑制性细胞(?)CD4+ Tregs。
Galectin-9,β半乳糖苷结合凝集素家族成员,可诱导嗜酸性粒细胞、肿瘤细胞和T细胞凋亡。通过Ca2+ -caspasel信号途径,galectin-9(?)(?)优先诱导活化CD4+T细胞发生凋亡。T细胞免疫球蛋白域和粘蛋白域蛋白-3(T-cell immunoglobulin domain and mucin domain protein-3, Tim-3), galectin-9的受体,选择性表达于终末分化Th1细胞,在Th17、Tregs表面也有一定的表达。Galectin-9在体内外均可以诱导Tim-3表达的细胞发生凋亡。有研究发现,galectin-9治疗可以有效的缓解实验性变态反应性脑炎,一种中枢神经系统脑炎。而且,在胶原诱导的关节炎动物模型以及HSV诱导的损伤模型中,galectin-9通过调节T细胞应答,如抑制Th17的产生,同时促进Tregs的分化和扩增,从而达到治疗疾病的目的。
在本研究中,我们用CVB3感染的雄性BALB/c小鼠,观察CVB3感染后心肌中galectin-9的表达变化,结果显示CVB3感染后雄性BALB/c小鼠心肌galectin-9的表达显著升高。进一步研究发现galectin-9可以促进Tregs的富集,并有效的缓解CVB3诱导的VMC。那么galectin-9是通过什么机制缓解VMC的发作?是影响病毒复制还是通过调节细胞免疫应答?Galectin-9促进Tregs富集的机制又是什么?因此,在本研究中我们利用CVB3感染的VMC模型,探讨了galectin-9在VMC发病中的作用及相关机制。
第一部分Galectin-9在病毒性心肌炎发病中的作用
一、CVB3感染前后galectin-9的表达变化
Galectins属于β半乳糖苷结合凝集素家族。现有的研究表明,galectins在各种生理或病理过程中发挥重要作用,如免疫炎症反应、肿瘤、动脉粥样硬化和糖尿病等。其中galectin-1,-3,-9在调节免疫应答和炎症反应中发挥重要作用。
为了研究galectins在CVB3诱导的VMC中的作用,我们首先观察了CVB3感染前后小鼠心肌中galectin-1,-3,-9的表达变化,结果发现CVB3感染可以显著上调小鼠心肌galectin-1,-9 mRNA的表达。由于galectin-1在病毒感染中研究较为清楚,我们进一步关注了CVB3感染前后galectin-9在不同组织中的表达变化,发现CVB3感染后,小鼠心肌、脾脏和肠系膜淋巴结中galectin-9 mRNA的表达显著升高。免疫组化结果也显示CVB3感染增加了小鼠心肌中galectin-9蛋白的表达。
上述结果提示,galectin-9可能参与了CVB3诱导的VMC的发病。
二、Galectin-9治疗前后BALB/c小鼠病毒性心肌炎严重程度的差异
VMC以心肌间质炎性细胞浸润为特征,导致心肌细胞灶性坏死,纤维化,最终导致心脏功能丧失。以CVB3感染小鼠建立心肌炎动物模型,很好地模拟了临床上VMC疾病过程。VMC的判断指标主要有体重减轻、血清学、病理学以及死亡率等。用galectin-9蛋白腹腔注射治疗CVB3感染雄性BALB/c小鼠,结果发现两组小鼠在感染后第3天体重都开始下降,其中未治疗组(PBS组)小鼠体重持续下降,至第7天体重减轻率达15%,而galectin-9治疗组BALB/c小鼠感染后第5天体重开始恢复,随后体重逐渐增加。从血清学指标来看,在感染后第7天,未治疗组BALB/c小鼠血清CK、CK-MB的活性显著升高,cTnI水平也明显升高；而galectin-9治疗组小鼠血清CK、CK-MB的活性和cTnI水平显著低于未治疗组小鼠。心脏组织HE染色显示未治疗组BALB/c小鼠心脏显示片状的炎性细胞浸润和心肌细胞坏死,而galectin-9治疗组小鼠心脏仅有少量炎性细胞浸润；治疗组小鼠心肌炎的炎症面积远小于未治疗组,而且治疗组小鼠心脏浸润CD45+单个核细胞比例显著降低。最后,从死亡率来看,至感染第10天,未治疗组BALB/c小鼠的死亡率高达70%,而galectin-9治疗组小鼠的死亡率仅为15%。综合上述各项指标可以看出,galectin-9治疗可以显著缓解CVB3诱导的VMC。
三、Galectin-9治疗对CVB3感染小鼠炎症性细胞因子分泌的影响
炎症性细胞因子如TNF-α、IFN-γ、IL-4和IL-10等在心肌炎的发病过程中发挥重要作用。因此,我们检测了galectin-9治疗对小鼠心脏局部和血清中炎性细胞因子TNF-α、IFN-γ、IL-4和IL-10分泌的影响,发现galectin-9治疗可以显著下调促炎性细胞因子TNF-a和IFN-y的分泌,同时促进抗炎性细胞因子IL-4和IL-10的分泌。
以上结果显示,galectin-9可以有效的缓解CVB3诱导的VMC,并促进细胞因子微环境向抗炎性转化,证实galectin-9的确参与了VMC的发病。
第二部分Galectin-9在病毒性心肌炎中的作用机制探讨
一、Galectin-9对病毒复制的影响
CVB3感染心肌细胞是诱发VMC的前提条件。由此我们必须排除一个可能即galectin-9缓解CVB3诱导的VMC是由于降低心肌病毒复制造成的。因此我们首先检测了galectin-9治疗前后CVB3感染的BALB/c小鼠心脏组织中CVB3病毒RNA数量和病毒滴度的变化,结果发现galectin-9并没有引起心脏组织中CVB3病毒RNA数量和病毒滴度的改变。
二、Galectin-9对细胞免疫应答的影响
由于galectin-9缓解VMC并没有降低心肌病毒复制,我们进一步探讨了galectin-9治疗对细胞免疫应答的影响。结果显示CVB3感染过程中,galectin-9可以显著降低小鼠心脏和脾脏中CD4+T细胞的比例,同时增加Tregs、CD11b+及Gr-1+细胞的数量。由于Tim-3 (galectin-9特异性受体)和TLR4的相互作用在VMC的发病过程中发挥重要作用,我们还检测了galectin-9对Tim-3和TLR4在免疫细胞表面表达的影响,发现galectin-9降低了CD4+T细胞Tim-3的表达,但其在巨噬细胞表面的表达显著升高；同时galectin-9显著降低了TLR4在CDllb+细胞及巨噬细胞表面的表达。
上述结果提示,galectin-9缓解CVB3诱导的VMC并不是直接降低病毒复制,而是通过调节细胞免疫应答参与心肌炎的发病,Tregs和CD11b+细胞可能参与其中。
前面的实验结果显示,galectin-9可以有效的缓解CVB3诱导的VMC,我们进一步探讨了其可能的细胞学机制以及是否这种作用依赖于效应T细胞数量的降低和Tregs数量的升高。
三、Galectin-9对于CD4+T细胞凋亡和增殖的影响
现有的研究表明,galectin-9可以优先诱导效应CD4+T细胞的凋亡,而在CVB3诱导的VMC模型中,分泌IFN-γ的CD4+T cells是影响疾病严重性的重要因素。因此,我们首先检测了galectin-9对CD4+T细胞凋亡的影响,发现galectin-9可以显著促进CD4+T细胞发生凋亡。进一步研究发现,galectin-9主要诱导CD4+CD2low/int效应T细胞凋亡(>90%),而对于CD4+CD25high Tregs的促凋亡作用甚微(<10%)。我们同时也检测了galectin-9对CD4+ T细胞增殖的影响,发现galectin-9能抑制CD4+T细胞增殖,并主要抑制CD4+CD25low/int效应T细胞的增殖,而并不影响CD4+CD25high Tregs的增殖。Galectin-9差异调节Tregs和效应T细胞凋亡和增殖可能是由于其受体Tim-3的表达差异造成的,相关机制仍需进一步研究。
四、Galectin-9在诱导调节性T细胞分化中的作用
Tregs在CVB3诱导的VMC的发病过程中发挥重要作用。为了探讨galectin-9是否影响Tregs应答,我们检测了galectin-9对Tregs分化的影响,发现galectin-9能促进CVB3感染的裸鼠心脏和脾脏中CD4+CD25-T细胞向Tregs转化。
五、Galectin-9在扩增CDllb+ Gr-1+细胞中的作用
前面的实验结果发现,galectin-9能显著增加CD11b+和Gr-1+细胞的比例,而CD11b和Gr-1是髓系来源抑制细胞(myeloid suppressor cells,MSCs)的特有表型,于是我们检测了galectin-9在调节CDl lb+Gr-1+细胞扩增中的作用,结果显示galectin-9能显著扩增CD11b+Gr-1+细胞。通过分析这群细胞的表型和细胞因子分泌情况,我们发现其具有髓系来源抑制细胞的表型。
许多研究表明,髓系来源抑制细胞可以促进Tregs的扩增。因此,我们接着研究了CD11b+Gr-1+细胞在扩增Tregs中的作用,结果显示,CD11b+Gr-1+细胞可以促进CD4+T细胞中Tregs的扩增,这种作用部分依赖于IL-10,而不依赖于TGF-β。
综上所述,本研究首次阐明了galectin-9在CVB3诱发的VMC发病中的作用；证实了galectin-9是通过调节细胞免疫应答参与了VMC的发病,并未影响病毒复制；多种机制参与了galectin-9对VMC的调节：Galectin-9差异调节效应T细胞和Tregs增殖和凋亡；CD11b+Gr-1+细胞的积累和Tregs的分化。本研究在一定程度上阐明VMC的发病机制,同时也为临床提供了一个有效的治疗靶点和理论支持。
The incidence and severity of heart disease, including myocarditis, is higher among men than women. Viral myocarditis (VMC), or inflammation of the heart, is a principal cause of heart failure in young adults often leading to chronic heart disease and dilated cardiomyopathy (DCM). Viral infection is one of the important reasons for VMC. Among the viruses, Coxsackievirus group B type 3 (CVB3) infection accounts for more than half of VMC cases. CVB3 is a member of the picomavirus family of small, non-enveloped, positive sense, RNA viruses, and are major etiological agents in clinical viral myocarditis. A murine model of CVB3 induced myocarditis has been established which mimicks many of the characteristics of the clinical disease. Although the pathogenesis of CVB3 infection has been studied for decades, it is only recently recognized that many variables, including viral genome structure, host genetic background, the age, and the immune status of the host, interact with each other to determine the initiation, occurrence and progression of viral myocarditis.
The bias of CD4+ Th immune response appears to influence the severity of myocarditis. On the one hand, the Thl immune response, rather than the Th2 immune response, is considered to be detrimental to heart tissue. Opavsky et al. found that the severity of disease is attenuated in CD4 knockout mice, confirming the role of CD4+ T cells in CVB3 induced myocarditis. Huber et al. found CD4+Thl cell responses are essential to CVB3 induced myocarditis susceptibility. On the other hand, regulatory T cells play a major role in protection against inflammation in the heart, and their alteration by viral infection may contribute substantially to the outcome of myocarditis. Recent studies have shown that autoimmune myocarditis and multiorgan inflammation are controlled by Foxp3+ T cells highly expressing the glucocorticoid-induced TNF receptor familyrelated protein (GITR). Depletion of the GITR+ T regulatory cells allowed activation of autoimmune heart disease. Huber and colleagues described myocarditis could be overcome by a coxsackievirus variant which maintained and induced regulatory T cells function.
Furthermore, cytokines play a key role in CVB3 induced myocarditis. In susceptible mice IL-1βand IL-18 play a significant role in the pathogenesis of CVB3 induced myocarditis. IL-1 or TNF-a can promote myocarditis in resistant B10.A mice. Our previous study indicated that exogenous administration of IL-4 is found to improve myocardial inflammation and the severity of myocarditis in mice infected with CVB3. Thus, therapeutic strategies of CVB3 induced myocarditis should consider regulation of regulatory T cells (Tregs) differentiation as well as inhibition of pro-inflammatory cells and Thl cytokines.
To shift the cytokine balance to anti-inflammatory cytokines and to delete pro-inflammatory Thl cells that closely associate with etiology of CVB3 induced myocarditis, it is necessary to discover novel biological substances that can selectively suppress the function or delete activated Thl cells, at the same time expanding Tregs. Galectin-9, one of the (3-galactoside binding animal lectins belonging to the galectin family, induces apoptosis of eosinophils, cancer cells, and T cells. Galectin-9 preferentially induces apoptosis of activated CD4+ T cells through Ca+ influx-calpain-caspasel pathway. Zhu et al. have recently demonstrated that galectin-9 is a ligand of T cell immunoglobulin- and mucin domain-containing molecule3 (TIM-3) that was expressed selectively on terminally differentiated Thl cells, Th17, Tregs, and that galectin-9 induces apoptosis of TIM-3-expressing cells in vitro and in vivo. Furthermore, exogenous administration of galectin-9 ameliorates experimental allergic encephalitis, an autoimmune disease of the central nervous system. More recently it has been shown that galectin-9 ameliorates a mouse collagen-induced arthritis (CIA) model and HSV induced lesions by suppressing the generation of Th17, promoting the induction of regulatory T cells.
In this study, we compared galectin-9 expression in different organs of males before and after CVB3 infection. Then we examined the effects of in vivo treatment with recombinant galectin-9 on the development of myocardial inflammation in male mice infected with CVB3. Meanwhile, we analyzed the modulation of immune cells in the heart and spleen of CVB3 infected male mice in vivo with or without recombinant galectin-9 treatment and explored the mechanisms involved.
The purpose of the present study was to clarify the role of galectin-9 in the development of murine acute myocarditis induced by CVB3 and its possible mechanisms involved.
1. Change of galectin-9 expression before and after CVB3 infection
Galectins are a family of animal lectins that bindβ-galactosides. Current research indicates that galectins play important roles in diverse physiological and pathological processes, including immune and inflammatory responses, tumour development and progression, neural degeneration, atherosclerosis, diabetes. Among these, galectin-1,-3,-9 are the key regulators of immune response and inflammation. To better understand the mechanisms responsible for increased heart disease in male mice, we first compared galectins expression in the heart from male BALB/c mice before and after CVB3 infection. We found galectin-9 mRNA expression as well as galectin-1 in the heart from males was up-regulated after CVB3 infection. Then we further focused on galectin-9 mRNA expression in different organs, and found it was significantly higher in the heart as well as spleen and mesenteric lymph node (MLN) after CVB3 infection by RT-PCR assessment. Subsequently we confirmed the higher expression of galectin-9 protein in the heart by immunohistochemistry after CVB3 infection.
2. Differential severity of CVB3 induced myocarditis before and after galectin-9 treatment
Viral myocarditis is characterized by inflammatory cells infiltration in the interstitial tissue of myocardium with the result of myocyte focal necrosis or fibrosis and finally the loss of heart function. It well mimics the characteristics of clinical viral myocarditis using CVB3 infected myocarditis murine model with the indices of serology, pathology and body weight reduced rate as well as mortality. From day 3 post-infection, the body weight of PBS treated mice decreased obviously. On day 7 post-infection, the body weight decreased 15%. While in galectin-9 treated mice, on day 3 post-infection, the body weight also reduced but then recovered on day 5. The activity of serum Creatine Kinase (CK) and MB isoenzyme of Creatine Kinase (CK-MB) was significantly down-regulated and the level of Cardiac Troponin I (cTnl) was also decreased in galectin-9 treated BALB/c mice on day 7 post-infection. The pathological studies, the most direct and important diagnosis criteria revealed that in PBS treated mice, on day 7 post-infection, H.E showed the focal infiltration of inflammatory cells and the massive necrosis of myocytes. While in galectin-9 treated mice, there was no obvious inflammatory cells infiltration and no myocyte necrosis. Moreover, lower frequency of CD45+ immune cells in the heart of galectin-9 treated mice than PBS treated mice confirmed the above histological findings. As far as mortality was concerned, the mortality in CVB3 infected male mice was 70%, which was much higher than that in galectin-9 treated mice with the mortality of 15%. From the above results, the conclusion could be drawn that galectin-9 alleviated the severity of viral myocarditis after CVB3 infection.
3. Effects of galectin-9 treatment on inflammatory cytokines production
Inflammatory cytokines, such as TNF-α, IFN-γ, IL-4 and IL-10 play a role in the initiation of inflammatory cell infiltration in the lesions. To clarify whether galectin-9 treatment regulates cytokines production, levels of inflammatory cytokines (TNF-α, IFN-γ, IL-4, IL-10) in myocardial tissue and serum from CVB3 infected mice were assessed with or without galectin-9 administration. CVB3 infection resulted in the increased levels of TNF-αand IFN-γin the mice. Galectin-9 treatment led to significant decreased levels of TNF-αand IFN-γin both myocardial tissue and serum of the infected mice, whereas galectin-9 increased the levels of IL-4 and IL-10. PartⅡPossible mechanisms underlies galectin-9 functions
1. Effects of galectin-9 treatment on CVB3 replication
CVB3 can infect myocytes and replicate in cells, which is the prerequisite to induce VMC. To exclude the possibility that galectin-9 could effectively rescue mice from lethal myocarditis was due to decreased CVB3 replication, the viral load in heart tissues was also assessed by real-time PCR and plaque assay, and it was found that galectin-9 treatment does not significantly change myocardial viral burden, suggesting that the alleviation of viral myocarditis by galectin-9 is not due to the direct down-regulation of viral replication.
2. Effects of galectin-9 treatment on immune response
Since alleviated inflammation in galectin-9 treated mice was not due to decreased viral replication in the heart, we next performed experiments to clarify whether galectin-9 modulates the balance of T immune response and influences the number of Tregs. Results showed that galectin-9 administration had significantly decreased percentage of CD4+ T cells, whereas it had remarkably increased percentage of Tregs as well as CDllb+ or Gr-1+ cells in heart and spleen from CVB3 infected mice. We further compared the level of Tim-3 (T cell Ig and mucin-3, the receptor of galectin-9) and TLR4 on immune cells isolated from the heart of males with or without galectin-9 treatment. Tim-3 expression was significantly reduced on CD4+ T cells but increased on macrophages from heart of males on day 7 p.i., while TLR4 expression was significantly reduced on CDllb+ cells and macrophages.
Since administration of galectin-9 alleviated CVB3 induced myocarditis, we addressed to analyze cellular mechanisms and whether the effects are entirely due to loss of pathogenic T cells and increased Tregs.
3. Influence of galectin-9 treatment on the apoptosis and proliferation of CD4+ T cells
Prior in vitro studies have indicated that galectin-9 triggering of pro-inflammatory CD4+ T cells causes them to undergo apoptosis. In the model of CVB3 induced myocarditis, since inflammation appeared to be mainly orchestrated by IFN-y producing CD4+ T cells, so we detected the effects of galectin-9 on the induction of apoptosis of CD4+ T cells. As shown in results, about 50% CD4+ T cells underwent apoptosis after galectin-9 treatment, perhaps accounting in part for the anti-inflammatory effect of galectin-9. Furthermore, while about 90% of CD4+CD25low/int effector T cells underwent apoptosis,10% of CD4+CD25high regulatory T cells were annexin V+
We further explored whether in vivo galectin-9 treatment would influence the proliferation of CD4+ T cells. As shown, BrdU+ proliferating CD4+ T cells increased in heart on day 7 after CVB3 infection, whereas it significantly decreased in mice receiving galectin-9 treatment. The decreased proliferative response mainly existed in the CD4+CD25low/int effector T cells.
These results indicated that in vivo galectin-9 administration efficiently down-regulated CD4+ T cell responses. The differential regulation of apoptosis and proliferation of effctor and regulatory T cells by galectin-9 maybe due to the differential expression of Tim-3.
4. Effects of galectin-9 treatment on the differentiation of regulatory T cells
In prior experiments have established that the severity of CVB3 induced myocarditis can be modulated by regulatory T cells. To determine whether galectin-9 administration to CVB3 infected mice had any influence on the Tregs response, experiments were done to clarify whether galectin-9 is involved in the differentiation of CD4+CD25+Foxp3+ Tregs. Thus, we transferred naive CD4+CD25-T cells into CVB3 infected nude mice on day 3 post-infection and galectin-9 was i.p. injected everyday till day 7. These mice were sacrificed on day 7 post-infection and heart infiltrated cells and splenocytes were separated, then the percentage of CD4+CD25+ Foxp3+ Tregs was determined by FACS. Results showed that there was a significant increase of CD4+ CD25+ Foxp3+ Tregs in the heart from galectin-9 treated mice compared to non-treated mice. In addition, the percentage of CD4+CD25+Foxp3+ Tregs in spleen from galectin-9 treated mice was significantly higher than non-treated mice. From the data described above, we clarified that galectin-9 promoted the induction of Tregs during CVB3 induced myocarditis in vivo.
5. Influence of galectin-9 treatment on expansion of myeloid suppressor cells
Galectin-9 treated animals, as compared with control animals, showed significantly expanded populations of CDllb+ and Gr-1+ cells, which phenotypes possessed by myeloid suppressor cells. So we detected the influence of galectin-9 treatment on expansion of CDllb+Gr-l+ cells. We found that galectin-9 promoted the expansion of CDllb+Gr-1+ cells, which expressed low level of F4/80, CD80,CD86 and IAd, a phenotypes possessed by myeloid suppressor cells. They also could secret IL-10 and TGF-β. Moreover, CDllb+Gr-1+ cells increased the number of regulatory T cells by expansion of previously existed cells, which partly depended on IL-10 production.
In conclusion, the present study demonstrated that galectin-9 may play a crucial role in CVB3 induced myocarditis and it may be one of the novel therapeutic candidates that can suppress autoimmune inflammation by regulating the T cell differentiation and the balance of pathogenic and regulatory T cells, such that pro-inflammatory cytokines production are inhibited and anti-inflammatory cytokines are enhanced.
引文
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