Consequences of Chemokine-Receptor Interactions with Che

总体而言，我的实验室专注于同源趋化因子配体和趋化因子模拟物与G蛋白偶联趋化因子受体的相互作用，以及由此产生的对炎症、自身免疫、癌症和疼痛的影响。我们已经证明，各种抗菌肽模拟趋化因子，也具有快速激活宿主免疫反应的能力。我们先前发现，a类和a类防御素都是对IDC具有趋化和激活作用以及体内免疫佐剂作用的警戒素。防御素与CCR6趋化因子受体相互作用，而防御素与未知的GiPCR相互作用。另一种抗菌肽长春花素(LL37)及其小鼠同源基因对表达在单核细胞和IDC前体细胞上的FPRL-1受体具有趋化作用，可诱导IDC成熟，在体内与明胶一样具有强大的佐剂作用。此外，我们已经证明，即使是从青蛙中获得的抗菌肽也可以与FPRL1阳性的哺乳动物细胞相互作用。显然，这些多肽的免疫功能在进化上是保守的。我们还研究了另一种名为嗜酸性粒细胞衍生神经毒素(EDN)的白细胞衍生警报蛋白的免疫激活和趋化作用，EDN是RNase家族的成员，具有抗病毒活性，包括抗HIV活性。EDN基于其与百日咳毒素敏感的GiPCR的相互作用，对IDC和MDC具有趋化作用。此外，基于与TLR2的相互作用，EDN可激活IDC产生多种促炎细胞因子，并成熟为MDC。初步数据显示，EDN在体内也有很强的免疫刺激作用。我们还发现高迁移率族蛋白I(HMGB1)是一种具有抗病毒活性的DNA结合蛋白，对IDC上的GiPCR具有趋化作用。我们的合作者Kevin Tracey博士等人已经证明HMGB1是一种有效的促炎细胞因子诱导剂，可以诱导IDC向MDC成熟，并在炎症部位高度产生。我们建议将这些早期预警信号称为“警报”。Alarmins对表达GI蛋白偶联受体(GiPCR)的白细胞具有趋化活性，并能诱导未成熟的树突状细胞(IDC)成熟为抗原提呈，T淋巴细胞激活MDC，从而产生体内免疫佐剂效应。如果与抗原一起使用，警报的这些活性会导致对该抗原的细胞和体液免疫反应的显著增强。因此，HMGB1也是一种警告。虽然这些警报蛋白在结构上是不同的，但它们可以迅速从白细胞颗粒中释放出来，或者由胃肠道、胃肠道和气管支气管树上的角质形成细胞或上皮细胞对促炎刺激做出反应而分泌。因此，这些尚未确定的警报很可能代表了向宿主防御系统发出危险信号的早期预警系统。像GM-CSF一样，一种细胞因子，也是一种基于其对树突状细胞的趋化作用和免疫佐剂作用的警示蛋白，这些警示蛋白可能被证明是肿瘤疫苗中有用的佐剂。GiPCR不仅与非同源的警示蛋白相互作用，还负责IDC对许多自身抗原和一些肿瘤抗原的趋化反应。我们先前报道了组氨酰tRNA合成酶(HRS)和AsnRS是一些肌炎患者产生自身抗体的自身抗原，它们分别对表达CCR5和CCR3的细胞(包括IDC)具有趋化作用。最近我们发现，在诱导实验性自身免疫性葡萄膜炎(EAU)的抗原中，IRBP使用CXCR3和CXCR5，而S抗原只使用CXCR3来趋化IDC。与I型糖尿病、EAE和硬皮病相关的许多其他自身抗原也对IDC具有趋化作用。

Overall, my laboratory focuses on the interactions of cognate chemokine ligands and chemokine mimics with G-protein coupled chemokine receptor and the resultant effects on inflammation, autoimmunity, cancer and algesia. We have shown that a variety of antimicrobial peptides mimic chemokines and also have the capacity to rapidly activate host immune responses. We previously identified both a and a types of defensins as alarmins with chemotactic and activating effects on iDC and in vivo immunoadjuvant effects. The a defensins interact with the CCR6 chemokine receptor, while a defensins interact with an as yet unknown GiPCR. Another antimicrobial peptide known as cathelicidin (LL37) and its murine homologue CRAMP are chemotactic for FPRL-1 receptors expressed on monocytes and precursors of iDC, induce the maturation of iDC and are equally as potent adjuvants in vivo as alum. Furthermore, we have shown that even antimicrobial peptides obtained from frogs interact with FPRL1 positive mammalian cells. Apparently the immune functions of these peptides have been evolutionarily conserved.We have also investigated the immune activating and chemotactic effects of another leukocyte granule derived alarmin known as eosinophil derived neurotoxin (EDN), which is a member of the RNAse family, and has antiviral activity including anti-HIV activity. EDN based on its interactions with a pertussis toxin susceptible GiPCR is chemotactic for iDC, and mDC. In addition, EDN based on interactions with TLR2 activates iDC to produce multiple proinflammatory cytokines and to mature into mDC. Preliminary data shows that EDN also has potent in vivo immunostimulating effects. We have also shown that High Mobility Group Box I (HMGB1), a DNA binding protein with antiviral activity, is chemotactic for a GiPCR on iDC. Our collaborators, Dr. Kevin Tracey, et al, have shown HMGB1 to be a potent inducer of proinflammatory cytokines, to induce the maturation of iDC to mDC and to be highly produced at inflammatory sites.We have proposed calling these early warning signals "alarmins". Alarmins are characterized by having chemotactic activity for leukocytes expressing Gi Protein Coupled Receptors (GiPCR), together with the capacity to induce immature dendritic cells (iDC) to mature into antigen- presenting, T lymphocyte activating mDC with resultant in vivo immunoadjuvant effects. These activities of alarmins, if administered together with an antigen, result in considerable augmentation of both cellular and humoral immune response to the antigen. HMGB1 is therefore also an alarmin. Although these alarmins are structurally distinct, they are rapidly released from granules of leukocytes or secreted in response to proinflammatory stimulants by keratinocytes or epithelial cells lining the GI tract, GU tract and tracheobronchial tree. As such, these and yet to be identified alarmins probably represent the early warning system to alert the host defense to danger signals. Like GM-CSF, a cytokine which is also an alarmin based on its chemotactic effect on dendritic cells and immunoadjuvant effects, these alarmins may prove useful as adjuvants in tumor vaccines.GiPCR not only interact with non-cognate alarmins, but also are responsible for the chemotactic responses of iDC to many autoantigens and some tumor antigens. We previously reported that histidyl tRNA synthetase (HRS) and AsnRS, autoantigens to which some patients with myositis develop auto-antibodies, are chemotactic for cells (including iDC) expressing CCR5 and CCR3 respectively. More recently we have shown that of the antigens that induce experimental autoimmune uveitis (EAU), IRBP uses CXCR3 and CXCR5, while S-antigen uses only CXCR3 to chemoattract iDC. Many other autoantigens associated with type I diabetes, EAE and scleroderma are also chemotactic for iDC.