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件组成，这些组件协同工作以减少 发病。 As a well-established member of the innate immune system, S100A12 is known to conduct 通过螯合锌离子发挥抗菌活性。这种隔离限制了病原体接触 Zn2+， 它们增殖的关键营养物质。此外，在感染过程中，S100A12 与膜相互作用 受体，例如晚期糖基化终末产物受体 (RAGE)，可启动促炎症反应 信号级联。尽管已知其参与抗菌和促炎活性，但 S100A12 的相互作用模式，特别是与膜受体的相互作用模式，尚不清楚。我们在这方面的目标 该提案的目的是表征 S100A12 的金属结合特性，使其能够发挥抗菌作用 活动并形成对 S100A12 与 RAGE 相互作用的原子尺度理解。我们建议这 相互作用是由其抗菌活性引发的，这使我们可以假设抗菌剂和亲 S100A12 的炎症活性是相互依赖的。 我们的研究表明，通过 Zn2+ 螯合的抗菌活性，S100A12 经历了自我修复 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。这些结果与文献中的报告相结合，证明了 血清和人体组织中存在寡聚 S100A12 物种，使我们能够提出一个方案 描述 S100A12 在免疫系统中的作用。该模型提出 S100A12 浓度依赖 细胞中的促炎作用是在其抗菌反应时启动的，从而建立了 其抗菌活性和促炎活性之间的相关性。为了检验我们的假设，我们提出 以下具体目标是表征 S100A12 抗菌功能及其寡聚物的作用：(i) 低聚 S100A12 组件中过渡金属离子配位环境的表征； (二) S100A12寡聚机制的鉴定； (iii) 确定依赖关系 S100A12 与 RAGE 的相互作用模式和寡聚化顺序。 这些拟议的研究将提供 S100A12-RAGE 的原子和分子水平快照 体外相互作用，这将为这些细胞之间的相互作用模式提供指导 体内的成分。符合我们揭示金属相关过程的原子细节的长期目标 在人类免疫反应中，该提案将深入了解金属依赖性自体免疫反应的作用 S100A12的组装。这些研究将增强对 S100A12 功能的理解并提供 为设计新疗法奠定基础。