Role of Formylpeptide Receptors in Host Defense

我们已经鉴定了A42肽用于诱导人巨噬细胞趋化性和活化的G蛋白偶联受体FPRL 1。FPRL 1最初被定义为细菌趋化性甲酰化肽fMLF的低亲和力受体，也被多种外源性和宿主衍生的趋化性多肽所共有。我们还发现，在与FPRL 1结合时，A42和FPRL 1复合物被内化到人巨噬细胞的细胞质区室中，并且长时间暴露于A42导致A42/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，尽管巨噬细胞短暂暴露于A42肽也导致A42肽摄入，但没有形成细胞聚集，表明巨噬细胞可以降解较低负荷的A42肽。在从新生小鼠中分离的小胶质细胞中，使用多种促炎剂（如Toll样受体（TLR）配体、TNF？、干扰素？并且CD 40增加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A42肽表现出有效的趋化活性，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一个传感器在中枢神经系统中过度产生的A42肽在AD中，介导炎症反应和A42肽的加工，这可能会决定AD病理的进展速度。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A42肽沉积水平的增加有关。因此，FPRL 1（mFPR 2）似乎在宿主防御AD中A42肽的积累和聚集中发挥重要作用。mFPR 2-/-小鼠也为我们提供了一个独特的工具，以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中，与野生型小鼠相比，mFPR 2-/-显示肺组织和支气管腔中的白细胞浸润显著减少，与对OVA的抗体反应减少相关。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和小鼠肺癌和黑色素瘤转移中的作用。

We have identified a G-protein coupled receptor FPRL1 used by A42 peptides to induce human macrophage chemotaxis and activation. FPRL1 was originally defined as a low-affinity receptor for the bacterial chemotactic formylated peptde fMLF and is also shared by a variety of exogenous and host-derived chemotactic polypeptides. We additionally found that upon binding to FPRL1, A42 and FPRL1 complexes were internalized into the cytoplasmic compartment of human macrophages and prolonged exposure to A42 resulted in the retention of A42/FPRL1 complexes in the cells, followed by formation of Congo-red positive fibrils. In contrast, although brief exposure of macrophages to A42 peptides also resulted in A42 peptide ingestion, there was no formation of fibrillary aggregation, suggesting a lower burden of A42 peptides could be degraded by macrophages. 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), TNF?, IFN? and CD40 increases the expression of mFPR2, a mouse counterpart of human FPRL1. Activated mouse microglial cells exhibited potent chemotactic activity to A42 peptides and ingest 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 A42 peptides in AD, and mediate inflammatory responses and for the processing of A42 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 of A42 peptide deposition. Thus, FPRL1 (mFPR2) appears to play an important role in host defense against the accumulation and aggregation of A42 peptides in AD. 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, as compared with wild type mice, mFPR2-/- showed markedly reduced leukocyte infiltration in the lung tissue and in the bronchial lumen, in association with reduce anti-body 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 metastasis of mouse lung cancer and melanoma.