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（由申请人提供）：巨噬细胞在诸如结核，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起着重要作用，以及疾病进展是否受到巨噬细胞的炎症性M1，不受浓度m1，富含m1的影响。人们认为，单核细胞为M1，M2A或M2REG的分化是响应在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成为M2REG巨噬细胞。 M2A巨噬细胞诱导和产生的信号与纤维化有关。纤维化动物模型中SAP的注射覆盖了这些信号，诱导M2REG分化并抑制纤维化。这些结果表明，SAP是一种构成型，并且在高水平上是先天免疫系统中的主要调节信号。 SAP是五糖反应性蛋白（CRP）和五糖蛋白3（PTX3）的五糖反应性蛋白（CRP）的成员。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，但是在某些动物模型中，CRP会增强炎症，而在其他模型中，CRP抑制了炎症。为了解决这种差异，我们发现CRP诱导单核细胞分化为MREG，但诱导巨噬细胞偏振成M1。为了深入了解用于调节先天免疫系统的基本机制，我们提出了三个特定的目的，以阐明五头蛋白用于调节巨噬细胞表型的分子机制。我们的第一个目的是检验以下假设：与巨噬细胞极化相比，五肽对巨噬细胞的分化可能不同，并检验了结合五肽蛋白会影响五肽信号传导的配体的假设。即使SAP，CRP和PTX3对巨噬细胞表型有明显的影响，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，其中一个或多个通过其他受体信号来调节巨噬细胞表型的模型。我们的第三个目标是确定人类足球俱乐部的贡献？对人类巨噬细胞表型的五肽调节的受体。然后，我们将使用此信息来筛选阻断给定五肽对给定FC的结合的化合物？受体，因此在五肽蛋白的存在下改变了巨噬细胞表型。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，并可能导致与巨噬细胞相关疾病的新疗法。