Consequences of Chemokine-Receptor Interactions with Che

总的来说，我的实验室主要研究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、癌症和痛觉的影响。我们已经表明，各种抗菌肽模拟趋化因子，也有能力迅速激活宿主免疫反应。我们之前发现a和a类型的防御素都是对iDC具有趋化和激活作用和体内免疫佐剂作用的警报器。a防御素与CCR6趋化因子受体相互作用，而a防御素与尚未知的gpcr相互作用。另一种抗菌肽被称为cathelicidin （LL37）及其小鼠同源物CRAMP，对单核细胞和iDC前体上表达的FPRL-1受体具有趋化作用，诱导iDC成熟，并且在体内与明矾一样是有效的佐剂。此外，我们已经证明，即使是从青蛙中获得的抗菌肽也能与FPRL1阳性的哺乳动物细胞相互作用。显然，这些肽的免疫功能在进化上是保守的。我们还研究了另一种白细胞颗粒来源的警报蛋白的免疫激活和趋化作用，称为嗜酸性神经毒素（EDN），它是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基因pcr的相互作用，对iDC和mDC具有趋化作用。此外，EDN基于与TLR2的相互作用，激活iDC产生多种促炎细胞因子，成熟为mDC。初步数据显示，EDN在体内也具有强大的免疫刺激作用。我们还发现，具有抗病毒活性的DNA结合蛋白High Mobility Group Box I （HMGB1）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是促炎细胞因子的有效诱导剂，可以诱导iDC向mDC的成熟，并在炎症部位大量产生。我们建议将这些早期预警信号称为“警报器”。警报器的特点是对表达Gi蛋白偶联受体（GiPCR）的白细胞具有趋化活性，同时能够诱导未成熟的树突状细胞（iDC）成熟为抗原呈递的T淋巴细胞，激活mDC，从而产生体内免疫佐剂作用。如果与抗原一起使用，这些警报器的活性会导致对抗原的细胞和体液免疫反应的显著增强。因此HMGB1也是一个警示。虽然这些警报在结构上是不同的，但它们从白细胞颗粒中迅速释放出来，或在促炎刺激物的作用下由胃肠道、GU道和气管支气管内的角质形成细胞或上皮细胞分泌。因此，这些尚未被识别的警报可能代表早期预警系统，提醒宿主防御危险信号。与GM-CSF（一种细胞因子，基于其对树突状细胞的趋化作用和免疫佐剂作用，也是一种警报素）一样，这些警报素可能被证明是肿瘤疫苗的佐剂。gpcr不仅与非同源报警蛋白相互作用，而且还负责iDC对许多自身抗原和一些肿瘤抗原的趋化反应。我们之前报道了组氨酸tRNA合成酶（HRS）和AsnRS，一些肌炎患者产生自身抗体的自身抗原，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抗原仅使用CXCR3来化学吸引iDC。许多其他与I型糖尿病、EAE和硬皮病相关的自身抗原也对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.