Mechanisms and Immune consequences of atypical efferocytosis of neutrophils during Porphyromonas gingivalis infection.

牙龈卟啉单胞菌感染期间中性粒细胞非典型胞吞作用的机制和免疫后果。

• 批准号: 10464584
• 负责人: Kelley N Cooper
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464584
• 关键词: Abate; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Area; Autoimmune Diseases; Bacterial Infections; Binding; Bypass; CREB1 gene; Cell physiology; Cells; Chronic; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Degradation Pathway; Digestion; Disease; Excision; Failure; Generations; Goals; Grant; Homeostasis; Immune; Immune Tolerance; In Situ; In Vitro; Infection; Inflammation; Inflammatory; Ingestion; Innate Immune Response; Kinetics; Knowledge; Left; Ligands; Link; Mediating; NF-kappa B; Necrosis; Neutrophil Infiltration; Oral; PTPN6 gene; Pathway interactions; Peptide Hydrolases; Periodontal Diseases; Periodontitis; Periodontium; Phagocytes; Phagosomes; Phenotype; Phosphatidylserines; Physiological; Porphyromonas gingivalis; Predisposition; Process; Production; Receptor Activation; Research Personnel; Resolution; Secondary Prevention; Signal Pathway; Signal Transduction; Site; Surface; Training; Trypsin; autoinflammatory; career; chronic infection; cytokine; design; gingipain; immune clearance; in vivo; insight; macrophage; neutrophil; new therapeutic target; novel; novel therapeutic intervention; oral pathogen; pathogen; pathogenic bacteria; periodontopathogen; receptor; receptor binding; response; skills; uptake

PROJECT SUMMARY/ABSTRACT Neutrophils recruited to the sites of bacterial infection or inflammation eventually undergo apoptosis and are cleared in situ by phagocytic cells such as macrophages. ‘Efferocytosis’ or the phagocytic uptake of apoptotic cells (AC), is a highly selective process that relies upon the recognition of apoptosis associated ligands, such as phosphatidylserine (PS), by efferocytic receptors on the engulfing cells. These interactions initiate downstream signaling that shuts down inflammatory pathways and orchestrates the hydrolytic breakdown of ACs within phagosomes/efferosomes for their eventual clearance. Several pathogens can manipulate efferocytosis in order to subvert immune clearance. We found that the periodontal pathogen Porphyromonas gingivalis uses a novel mechanism to dysregulate efferocytosis by causing the uptake of live neutrophils in a PS independent manner, possibly bypassing engagement and/or activation of PS binding efferocytic receptors. Our preliminary data show that this atypical efferocytosis of live cells resulted in sustained production of pro- inflammatory cytokines and a profound failure of macrophages to activate pro-resolution pathways. We hypothesize that P. gingivalis mediated atypical efferocytosis perpetuates inflammation in periodontal disease and breakdown of immune tolerance. In Aim 1 of this proposal, we will delineate specific signaling pathways that mechanistically link ingestion of live neutrophils to the generation of proinflammatory cytokines. In Aim 2 of this proposal, we will determine whether ingestion of live neutrophils results in degradation delays due to incomplete maturation of the efferosomes, resulting in diminished hydrolytic capacity. Defects in clearance of ACs within efferosomes is increasingly linked to chronic inflammation and autoinflammatory sequalae in a large number of diseases. Overall, the data generated from this grant will not only shed mechanistic insights atypical efferocytosis caused by a P. gingivalis but will also be useful in designing new therapeutic approaches to abate chronic inflammation associated with periodontitis. Furthermore, this application includes a comprehensive training plan that will enable me to strengthen my ability to define scientific questions and answer them using the strong technical skillset and conceptual understanding. I will continue to expand my expertise in areas of host-pathogen interactions, innate immune responses, and cellular signaling pathways and the knowledge and skill sets gained from the proposed training will be invaluable moving forward as I pursue a career as an independent investigator.

项目总结/摘要 募集到细菌感染或炎症部位的中性粒细胞最终经历凋亡， 由巨噬细胞等吞噬细胞原位清除。“胞饮作用”或细胞凋亡的吞噬摄取 细胞凋亡（AC）是一个高度选择性的过程，依赖于细胞凋亡相关配体的识别， 如磷脂酰丝氨酸（PS），通过吞噬细胞上的巨噬细胞受体。这些互动开始 下游信号传导，关闭炎症通路，并协调 吞噬体/溶酶体内的AC用于其最终清除。几种病原体可以操纵 以破坏免疫清除。我们发现牙周病病原体卟啉单胞菌 牙龈炎使用一种新的机制，通过引起嗜中性粒细胞的摄取， PS独立的方式，可能绕过PS结合巨噬细胞受体的接合和/或激活。 我们的初步数据表明，这种活细胞的非典型胞浆细胞增多导致持续的促红细胞生成， 炎性细胞因子和巨噬细胞激活促消退途径的严重失败。我们 假设牙龈卟啉单胞菌介导非典型性牙周细胞增多症使牙周病炎症持续存在 和免疫耐受性的破坏。在本提案的目标1中，我们将描述特定的信号通路 其在机制上将嗜中性粒细胞的摄取与促炎细胞因子的产生联系起来。在目标2中 根据这项建议，我们将确定摄入活的中性粒细胞是否会导致降解延迟， 不完全成熟的蛋白质体，导致水解能力减弱。清关缺陷 在慢性炎症和自身炎性后遗症中，染色体内的AC越来越多地与慢性炎症和自身炎性后遗症相关。 大量的疾病。总的来说，从这笔赠款中产生的数据不仅会摆脱机械的见解， 由牙龈卟啉单胞菌引起的非典型性细胞增多症，但也将有助于设计新的治疗方法 以减轻与牙周炎相关的慢性炎症。此外，该应用程序包括一个 全面的培训计划，使我能够加强我定义科学问题的能力， 使用强大的技术技能和概念理解来回答这些问题。我将继续扩大我的 在宿主-病原体相互作用、先天免疫反应和细胞信号传导途径领域的专业知识 从拟议的培训中获得的知识和技能将是非常宝贵的， 成为一名独立调查员