Interdependence of Antimicrobial and Pro-inflammatory Activities Mediated byS100A12 in the Innate Immune Response

先天免疫反应中 S100A12 介导的抗菌和促炎活性的相互依赖性

• 批准号: 9812550
• 负责人: Rupal Gupta
• 金额: $ 46.51万
• 依托单位: COLLEGE OF STATEN ISLAND
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812550
• 关键词: Address; Binding; Biochemical; Biophysics; Calcium; Cells; Chemicals; Communication; Complex; Computing Methodologies; Dependence; Disease; EF Hand Motifs; Environment; Equilibrium; Extracellular Space; Goals; Human; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Investigation; Ions; Ligands; Literature; Mediating; Membrane; Metal Binding Site; Metals; Methodology; Modeling; Molecular; Molecular Weight; Nature; Nutrient; Outcome; Pathogenesis; Pathogenicity; Play; Process; Property; Proteins; Reporting; Research; Role; S100 Proteins; S100A12 gene; Scheme; Serum; Signal Transduction; Structure; Systems Development; Testing; Therapeutic; Transition Elements; Variant; Virulence; Work; Zinc; antimicrobial; base; combat; design; diagnostic biomarker; dimer; human tissue; in vitro Model; in vivo; inflammatory marker; insight; member; molecular assembly/self assembly; novel therapeutics; overexpression; pathogen; programs; quantum; receptor; receptor for advanced glycation endproducts; response; self assembly; therapeutic development

The human innate immune system is composed of several components that work in conjunction to curtail pathogenesis. As a well-established member of the innate immune system, S100A12 is known to conduct antimicrobial activities via sequestration of zinc ions. This sequestration limits the pathogen's access to Zn2+, a critical nutrient for their proliferation. Furthermore, during infection, S100A12 interacts with membrane receptors such as the receptor for advanced glycation end products (RAGE) to initiate a pro-inflammatory signaling cascade. Although known to participate in both antimicrobial and pro-inflammatory activities, the mode of interaction of S100A12, particularly with the membrane receptors, is not known. Our goal in this proposal is to characterize the metal binding properties of S100A12 that allow it to perform antimicrobial activities and develop an atomic scale understanding of interaction of S100A12 with RAGE. We propose that this interaction is initiated by its antimicrobial activities allowing us to hypothesize that the antimicrobial and pro- inflammatory activities of S100A12 are interdependent. Our studies demonstrate that by the antimicrobial activity of Zn2+ sequestration, S100A12 undergoes self- assembly leading to the formation of oligomers. We also show that this self-assembly is dependent on the concentration of S100A12. These results, in conjunction with reports in the literature demonstrating the presence of oligomeric S100A12 species in blood serum and human tissues, have allowed us to propose a scheme describing the role of S100A12 in the immune system. This model proposes S100A12 concentration dependent pro-inflammatory actions in cells that are initiated upon its antimicrobial responses, thereby establishing a correlation between its antimicrobial and pro-inflammatory activities. To test our hypothesis, we propose the following specific aims to characterize S100A12 antimicrobial functions and the role of its oligomers: (i) characterization of the coordination environment of transition metal ions in oligomeric S100A12 assemblies; (ii) identification of the mechanism of oligomerization of S100A12; and (iii) determination of the dependence of the mode of interaction of S100A12 with RAGE and the order of oligomerization. These proposed studies will provide atomic- and molecular-level snapshots of the S100A12-RAGE interactions in vitro, which will provide guidance for the mode of the interaction between these cellular components in vivo. In line with our long-term goal to unravel atomistic details of metal-dependent processes in the human immune response, this proposal will provide insights into the role of metal dependent self- assembly of S100A12. These studies will enhance the understanding of the functioning of S100A12 and provide basis for the design of novel therapeutics.

人类先天免疫系统由几个组成部分组成，这些组件可以限制 发病。作为先天免疫系统的成员，已知S100A12进行 锌离子的隔离性抗菌活性。这种隔离限制了病原体对Zn2+的访问 其增殖的关键营养素。此外，在感染期间，S100A12与膜相互作用 诸如晚期糖基化末端产物（RAGE）的受体启动促炎的受体 信号级联。尽管众所周知可以参与抗菌和促炎性活动，但 S100A12的相互作用模式，尤其是与膜受体的相互作用。我们的目标 建议是表征S100A12的金属结合特性，该特性使其可以执行抗菌剂 活动并发展对S100A12与愤怒的相互作用的原子量规模的理解。我们提出这一点 相互作用是由其抗菌活性引发的 S100A12的炎症活动是相互依存的。 我们的研究表明，通过Zn2+隔离的抗菌活性，S100A12经历了自我 组装导致低聚物的形成。我们还表明，这种自组装取决于 S100A12的浓度。这些结果，以及文献中的报告证明了 血清和人体组织中的寡聚S100A12物种的存在使我们能够提出一种方案 描述S100A12在免疫系统中的作用。该模型提出了S100A12浓度依赖性 细胞中促炎作用是在其抗菌反应上引发的，从而建立了 其抗菌和促炎活性之间的相关性。为了检验我们的假设，我们提出了 以下特定目的是表征S100A12抗菌功能及其低聚物的作用：（i） 寡聚S100A12组件中过渡金属离子协调环境的表征； （ii） 识别S100A12的寡聚机理； （iii）确定 S100A12与愤怒的相互作用模式和寡聚的顺序。 这些提出的研究将提供S100A12-RAGE的原子和分子级快照 体外相互作用，这将为这些细胞之间的相互作用方式提供指导 体内组件。符合我们的长期目标，以揭示金属依赖性过程的原子性细节 在人类的免疫反应中，该提案将提供有关金属依赖性自我作用的见解 S100A12组装。这些研究将增强对S100A12功能的理解，并提供 新型治疗学设计的基础。