Role of Formylpeptide Receptors in Host Defense

我们已经鉴定了FPRL 1和mFPR 2作为人和小鼠骨髓细胞上的受体， 介导细胞对多种病原体和宿主衍生肽的趋化性，包括血清 淀粉样蛋白A（SAA）和与阿尔茨海默病（AD）相关的淀粉样蛋白β肽。我们 另外发现，在与小胶质细胞上的FPRL 1或mFPR 2结合后， 脑巨噬细胞、淀粉样蛋白β 42和FPRL 1复合物被内化到细胞质中， 长期暴露于淀粉样蛋白（A）β 42导致细胞的保留 淀粉样蛋白β 42/FPRL 1复合物在细胞中的表达，随后形成刚果红阳性 纤维相反，巨噬细胞/小神经胶质细胞短暂暴露于A β 42肽也 导致Abeta 42肽摄入，但没有形成纤维聚集， 这表明可以降解较低负荷的Abeta 42肽。在分离的小胶质细胞中 从新生小鼠，用各种促炎剂如用于治疗炎症的配体治疗， Toll样受体（TLR）、TNF α、IFN γ和CD 40增加mFPR 2的表达， 人类FPRL 1的小鼠对应物。激活的小鼠小胶质细胞表现出强大的 对淀粉样蛋白β 42肽的趋化反应，并通过 受体mFPR 2。我们的观察表明，FPRL 1和它的小鼠对应物可能作为一种免疫调节剂。 CNS中的传感器，用于AD中观察到的过量产生的A β 42肽。Abeta42-FPRL1（mFPR2） 内在化导致促炎介质的产生， A β 42肽，其可决定AD病理学的进展速率。更 精确评估FPRL 1（mFPR 2）在先天宿主防御，炎症和免疫反应中的作用。 为了研究AD的发病机制，我们已经产生了mFPR 2缺失的小鼠品系。我们正在进行的研究 研究表明，在AD小鼠模型中，mFPR 2的缺失减少了激活的细胞数量 小胶质细胞在脑内的相关性水平增加， Abata 42肽沉积的分布。因此，FPRL 1（mFPR 2）似乎起重要作用。 在宿主防御中的作用有利于吞噬小胶质细胞中Abeta 42肽的积累 细胞，从而促进清除并减少AD中的损伤。mFPR 2-/-小鼠的产生 这也为我们研究这种受体在其他促炎性疾病中的作用提供了一种独特的工具。 和免疫疾病以及癌症的发展。我们在卵清蛋白中发现 （OVA）诱导的炎症和免疫反应的肺部疾病模型，与野生型 型小鼠，mFPR 2-/-显示肺组织中的白细胞浸润显著减少， 支气管腔，与减少的抗体反应，以卵清蛋白。因此，我们的研究 表明mFPR 2在对外来抗原炎症和免疫应答中的关键作用。进一步 正在进行研究以确定mFPR 2在炎症性肠病诱导的炎症性肠病中的作用。 结肠癌和小鼠肺癌和黑色素瘤转移的发展。

We have identified FPRL1 and mFPR2 as receptors on human and mouse myeloid cells that mediate cell chemotaxis to a variety of pathogen and host derived peptides, including serum amyloid A (SAA) and amyloid beta peptides associated with Alzheimer's disease (AD). We additionally found that upon binding to FPRL1 or mFPR2 on migcroglial cells, considered as brain macrophages, Amyloid beta42 and FPRL1 complexes were internalized into the cytoplasmic compartment of the cells and prolonged exposure to Amyloid(A) beta42 resulted in the retention of Amyloid beta42/FPRL1 complexes in the cells, followed by formation of Congo-red positive fibrils. In contrast, brief exposure of macrophages/microglial cells to Abeta42 peptides also resulted in Abeta42 peptide ingestion, but without formation of fibrillary aggregation, suggesting a lower burden of Abeta42 peptides could be degraded. In microglial cells isolated from new born mice, treatment with a variety of proinflammatory agents such as the ligands for the Toll like receptors (TLRs), TNFalpha, IFNgamma and CD40 increases the expression of mFPR2, the mouse counterpart of human FPRL1. Activated mouse microglial cells exhibited potent chemotactic responses to Amyloid beta42 peptides and ingested the peptides through the receptor mFPR2. Our observations suggest that FPRL1 and its mouse counterpart may act as a sensor in the CNS for over produced Abeta42 peptides seen in AD. Abeta42-FPRL1(mFPR2) internalization results in production of proinflammatory mediators and the processing of Abeta42 peptides, which may determine the rate of the progression of AD pathology. To more precisely evaluate the role of FPRL1 (mFPR2) in innate host defense, inflammation and in the pathogenesis of AD, we have generated a mouse strain depleted of mFPR2. Our ongoing studies have revealed that in a mouse model of AD, depletion of mFPR2 reduced the number of activated microglial cells in the brain in association with increased level and more diffused distribution of Abata42 peptide deposition. Thus, FPRL1 (mFPR2) appears to play an important role in host defense favoring the accumulation of Abeta42 peptides in phagocytic microglial cells thus facilitating clearance and reducing damage in AD. The generation of mFPR2-/- mice also provide us with a unique tool to study the role of this receptor in other proinflammtory and immune diseases as well as in the development of cancer. We found that in an ovalbumin (OVA)-induced inflammatory and immune response model of lung disease, as compared with wild type mice, mFPR2-/- showed markedly reduced leukocyte infiltration in the lung tissue and in the bronchial lumen, in association with reduced antibody responses to OVA. Thus our studies suggest a key role of mFPR2 in inflammatory and immune responses to foreign antigen. Further studies are underway to determine the role of mFPR2 in inflammatory bowel disease-induced colon cancer and in the development of metastasis in mouse lung cancer and melanoma.