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，其介导细胞对病原体和宿主衍生肽的趋化性，所述宿主衍生肽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。我们已经发现，在与被认为是脑巨噬细胞的小胶质细胞上的FPRL 1或mFPR 2结合后，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，并且长期暴露于淀粉样蛋白（A）β 42导致淀粉样蛋白β 42/FPRL 1复合物保留在细胞中，随后形成刚果红阳性原纤维。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A β 42肽摄入，但没有形成细胞聚集，表明可以降解较低负荷的A β 42肽。 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（TLR）、TNF α、IFN γ和CD 40的配体处理增加了mFPR 2（人FPRL 1的小鼠对应物）的表达。活化的小鼠小胶质细胞对淀粉样蛋白β 42肽表现出有效的趋化反应，并通过受体mFPR 2摄取肽。我们的观察结果表明，FPRL 1和它的小鼠对应物可以作为传感器在中枢神经系统中的过度产生的A β 42肽在AD中看到。A β 42-FPRL 1（mFPR 2）内化导致促炎介质的产生和A β 42肽的加工，这可能决定AD病理学的进展速率。为了更精确地评估FPRL 1（mFPR 2）在先天宿主防御、炎症和AD发病机制中的作用，我们产生了mFPR 2缺失的小鼠品系。我们正在进行的研究表明，在AD小鼠模型中，mFPR 2的耗竭减少了脑中活化的小胶质细胞的数量，这与Abata 42肽沉积的水平增加和分布更分散有关。因此，FPRL 1（mFPR 2）似乎在宿主防御中起重要作用，有利于吞噬性小胶质细胞中A β 42肽的积累，从而促进AD中的清除并减少损伤。 mFPR 2-/-小鼠的产生也为我们提供了一个独特的工具来研究这种受体在其他促炎性和免疫性疾病以及癌症发展中的作用。我们发现，在卵清蛋白（OVA）诱导的炎症和免疫反应模型的肺部疾病，与野生型小鼠相比，mFPR 2-/-显示显着减少白细胞浸润的肺组织和支气管腔，与减少抗体反应的OVA。因此，我们的研究表明mFPR 2在炎症和免疫应答中对外源抗原的关键作用。进一步的研究正在进行中，以确定mFPR 2在炎症性肠病诱导的结肠癌中的作用，以及在小鼠肺癌和黑色素瘤转移的发展中的作用。

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.