Role of Formylpeptide Receptors in Host Defense

FPRL 1和mFPR 2是人和小鼠骨髓细胞上的受体，其介导细胞凋亡。 对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β肽。我们发现， 与被认为是脑巨噬细胞的小胶质细胞上的FPRL 1或mFPR 2结合，淀粉样蛋白 β 42和FPRL 1复合物被内化到细胞的细胞质区室中， 长期暴露于淀粉样蛋白（A）β 42导致淀粉样蛋白β 42/FPRL 1的保留 复合物在细胞中，随后形成刚果红阳性原纤维。与此相反， 将巨噬细胞/小神经胶质细胞短暂暴露于A β 42肽也导致A β 42 肽摄入，但没有形成蛋白质聚集，表明负荷较低 的Abeta 42肽可以被降解。在从新生小鼠分离的小胶质细胞中， 用多种促炎剂如Toll样受体的配体治疗 受体（TLR）、TNF α、IFN γ和CD 40增加mFPR 2的表达，小鼠 人FPRL 1的对应物。激活的小鼠小胶质细胞表现出强的趋化性 对淀粉样蛋白β 42肽的应答，并通过受体mFPR 2摄取肽。我们 观察表明，FPRL 1及其小鼠对应物可能作为CNS中的传感器， 在AD中观察到过量产生的Abeta 42肽。Abeta 42-FPRL 1（mFPR 2）内化导致 促炎介质的产生和A β 42肽的加工， 确定AD病理学进展的速率。为了更准确地评估 FPRL 1（mFPR 2）在先天宿主防御、炎症和AD发病机制中的作用，我们已经 产生mFPR 2耗尽的小鼠品系。我们正在进行的研究表明， 在AD模型中，mFPR 2的缺失减少了脑中活化的小胶质细胞的数量 与Abata 42肽水平增加和分布更分散有关 证词因此，FPRL 1（mFPR 2）似乎在宿主防御中起重要作用，有利于宿主的免疫应答。 A β 42肽在吞噬性小胶质细胞中的积累，从而促进清除 减少AD的损害。mFPR 2-/-小鼠的产生也为我们提供了一个独特的工具， 研究这种受体在其他促炎性和免疫性疾病以及 癌症的发展。我们发现，在卵清蛋白（OVA）诱导的炎症和免疫反应中， 与野生型小鼠相比，mFPR 2-/-小鼠在肺疾病应答模型中表现出显著的 减少肺组织和支气管腔内的白细胞浸润， 对卵清蛋白的抗体反应降低。因此，我们的研究表明mFPR 2在以下方面的关键作用： 炎症和对外来抗原免疫反应。进一步的研究正在进行中， 确定mFPR 2在炎症性肠病诱导的结肠癌中的作用， 小鼠肺癌和黑色素瘤转移的发展。

FPRL1 and mFPR2 are receptors on human and mouse myeloid cells that mediate cell chemotaxis to a pathogen and host derived peptides, including serum amyloid A (SAA) and amyloid beta peptides associated with Alzheimer's disease (AD). We have 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 provides 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.