Pentraxin regulation of macrophage differentiation

Pentraxin对巨噬细胞分化的调节

• 批准号: 8691360
• 负责人: Richard H Gomer
• 金额: $ 35.21万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691360
• 关键词: Affect; Amyloid; Animal Model; Asthma; Atherosclerosis; Autoimmune Diseases; Binding; Biological Assay; Blood; Cells; Chronic; Data; Disease; Disease Progression; Environment; Family; Fc Receptor; Fibrosis; Goals; Human; Immune system; Immunoglobulin G; Infection; Inflammation; Inflammatory; Injection of therapeutic agent; Knockout Mice; Lead; Leishmania; Ligand Binding; Ligands; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Nomenclature; Obesity; PTX3 protein; Phenotype; Plasma; Plasma Proteins; Play; Polysaccharides; Preclinical Drug Evaluation; Production; Property; Protein Family; Proteins; Regulation; Resistance; Resolution; Role; Serum; Serum Proteins; Signal Transduction; Signaling Protein; Small Interfering RNA; Surface; System; Testing; Therapeutic; Tuberculosis; Work; cytokine; drug candidate; functional outcomes; high risk; inflammatory marker; insight; macrophage; member; monocyte; novel; novel therapeutics; pathogen; public health relevance; receptor; repaired; response; small molecule; tissue repair

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.

描述（申请人提供）：巨噬细胞在结核病、利什曼原虫、慢性炎症、自身免疫性疾病、动脉粥样硬化、肥胖、哮喘、纤维化和癌症等疾病中发挥重要作用，并且巨噬细胞是否具有炎症对疾病进展有很大影响M1、促纤维化 M2a 或免疫调节 M2reg。单核细胞分化为 M1、M2a 或 M2reg 被认为是响应炎症或修复过程中释放的信号而发生的。出乎意料的是，一种称为血清淀粉样蛋白 P (SAP) 的组成型血浆蛋白会诱导单核细胞变成 M2reg 巨噬细胞。 M2a 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 会覆盖这些信号，诱导 M2reg 分化并抑制纤维化。这些结果表明 SAP 是先天免疫系统中的一种组成型信号，并且在高水平上是一种占主导地位的调节信号。 SAP 是 pentraxin 家族的成员，该家族包括 C-多糖反应蛋白 (CRP) 和 pentraxin-3 (PTX3)。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。为了解决这一差异，我们发现 CRP 诱导单核细胞分化为 Mreg，但诱导巨噬细胞极化为 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目标来阐明五聚蛋白用于调节巨噬细胞表型的分子机制。我们的首要目标是检验五聚蛋白对巨噬细胞分化与巨噬细胞极化具有不同影响的假设，并检验结合五聚蛋白的配体影响五聚蛋白信号传导的假设。尽管 SAP、CRP 和 PTX3 对巨噬细胞表型有不同的影响，但它们都与 Fc? 结合？细胞上的受体。我们的第二个目标是区分 SAP 激活某些 Fc 的模型？受体和 CRP（和/或 PTX3）激活其他 Fc？受体和模型，其中一种或多种五聚蛋白通过其他受体发出信号来调节巨噬细胞表型。我们的第三个目标是确定人类 Fc 的贡献？五聚蛋白受体对人类巨噬细胞表型的调节。然后，我们将使用该信息来筛选能够阻断给定五聚蛋白与给定 Fc 结合的化合物？受体，因此在五聚蛋白存在的情况下，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，并可能带来巨噬细胞相关疾病的新疗法。