Pentraxin regulation of macrophage differentiation

描述（由申请人提供）：巨噬细胞在诸如结核病、利什曼原虫、慢性炎症、自身免疫性疾病、动脉粥样硬化、肥胖症、哮喘、纤维化和癌症的疾病中起主要作用，并且疾病进展受到巨噬细胞是炎性M1、促纤维化M2 a还是免疫调节性M2 reg的强烈影响。单核细胞分化为M1、M2 a或M2 reg被认为是对炎症或修复过程中释放的信号的响应。出乎意料的是，称为血清淀粉样蛋白P（SAP）的组成型血浆蛋白诱导单核细胞变成M2 reg巨噬细胞。由M2 a巨噬细胞诱导和产生的信号与纤维化相关。在纤维化动物模型中注射SAP覆盖这些信号，诱导M2 reg分化，并抑制纤维化。这些结果表明，SAP是先天免疫系统中的组成性调节信号，并且在高水平下是显性调节信号。SAP是五聚蛋白家族的成员，该家族包括C-多糖反应蛋白（CRP）和五聚蛋白-3（PTX 3）。尽管CRP与SAP具有很强的序列和结构相似性，但CRP是炎症的主要标志物，但在一些动物模型中，CRP增强炎症，而在其他模型中，CRP抑制炎症。为了解决这一矛盾，我们发现CRP诱导单核细胞分化为Mreg，但诱导巨噬细胞分化为M1。为了深入了解用于调节先天免疫系统的基本机制，我们提出了三个具体的目标来阐明五聚素调节巨噬细胞表型的分子机制。我们的第一个目的是测试的假设，pentraxins可以有不同的影响巨噬细胞分化相比，巨噬细胞极化，并测试的假设，即结合pentraxins的配体影响pentraxin信号。尽管SAP、CRP和PTX 3对巨噬细胞表型有不同的影响，但它们都与Fc？细胞上的受体。我们的第二个目标是区分模型SAP激活一些Fc？受体和CRP（和/或PTX 3）激活其他Fc？受体，以及其中一种或多种正五聚素通过其它受体发出信号以调节巨噬细胞表型的模型。我们的第三个目标是确定人类Fc？正五聚蛋白受体对人巨噬细胞表型的调节。然后，我们将使用这些信息来筛选化合物，阻止一个给定的正五聚蛋白结合到一个给定的Fc？受体，并因此在五聚蛋白的存在下，改变巨噬细胞表型。总之，这项工作将有助于阐明先天免疫系统用于调节巨噬细胞分化的新机制，并可能导致巨噬细胞相关疾病的新疗法。

DESCRIPTION (provided by applicant): Macrophages play a major role in diseases such as tuberculosis, Leishmania, chronic inflammation, autoimmune diseases, atherosclerosis, obesity, asthma, fibrosis, and cancer, and the disease progression is strongly affected by whether the macrophages are inflammatory M1, profibrotic M2a, or immunoregulatory M2reg. The differentiation of monocytes into M1, M2a, or M2reg has been thought to occur in response to signals released during inflammation or repair. Unexpectedly, a constitutive blood plasma protein called Serum Amyloid P (SAP) induces monocytes to become M2reg macrophages. Signals inducing and produced by M2a macrophages are associated with fibrosis. Injections of SAP in animal models of fibrosis override these signals, induce M2reg differentiation, and inhibit fibrosis. These results suggest that SAP is a constitutive, and at high levels a dominant, regulatory signal in the innate immune system. SAP is a member of the pentraxin family that includes C-polysaccharide reactive protein (CRP) and pentraxin-3 (PTX3). Although CRP has strong sequence and structural similarity to SAP, CRP is a major marker of inflammation, but in some animal models CRP potentiates inflammation, and in other models CRP inhibits inflammation. In an effort to resolve this discrepancy, we found that CRP induces the differentiation of monocytes into Mreg, but induces macrophages to polarize into M1. To gain insight into a fundamental mechanism used to regulate the innate immune system, we propose three specific aims to elucidate the molecular mechanism used by pentraxins to regulate macrophage phenotype. Our first aim is to test the hypothesis that pentraxins can have different effects on macrophage differentiation compared to macrophage polarization, and test the hypothesis that ligands that bind pentraxins affect pentraxin signaling. Even though SAP, CRP, and PTX3 have distinct effects on macrophage phenotype, they all bind to Fc? receptors on cells. Our second aim is to distinguish between models where SAP activates some Fc? receptors and CRP (and/or PTX3) activates other Fc? receptors, and models where one or more of the pentraxins signals through other receptors to regulate macrophage phenotype. Our third aim is to determine the contribution of human Fc? receptors to pentraxin regulation of human macrophage phenotype. We will then use this information to screen for compounds that block the binding of a given pentraxin to a given Fc? receptor, and thus in the presence of the pentraxin, alter macrophage phenotype. Together, this work will help to elucidate a novel mechanism used by the innate immune system to regulate macrophage differentiation, and may lead to new therapies for macrophage-associated diseases.