Role of Peritoneal Macrophage in Spontaneous Bacterial Peritonitis

腹膜巨噬细胞在自发性细菌性腹膜炎中的作用

• 批准号: 10753019
• 负责人: Takeshi Saito
• 金额: $ 54.62万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753019
• 关键词: Animal Model; Anti-Bacterial Agents; Antibacterial Response; Architecture; Ascites; Cells; Characteristics; Cirrhosis; Complication; Deterioration; Development; Digestion; Down-Regulation; Effectiveness; Equilibrium; Exhibits; Exposure to; Frequencies; Functional disorder; Goals; Human; Immune; Immune Tolerance; Immunity; Immunologics; Impairment; In Vitro; Infection; Infection Control; Inflammation Mediators; Intestines; Invaded; Investigation; Knowledge; Maintenance; Microbe; Modeling; Molecular; Morbidity - disease rate; Natural Immunity; Neutrophil Activation; Neutrophil Infiltration; Omentum; Patients; Pattern; Peritoneal; Peritoneal Fluid; Peritoneal Macrophages; Peritoneum; Peritonitis; Process; Production; Property; Public Health; Rattus; Research; Role; Spottings; Stromal Cells; Testing; Virulence; Vitamin A; Vitamin A Deficiency; antimicrobial; bactericide; cell type; chemokine; cytokine; design; gut dysbiosis; gut microbiota; in vivo; insight; mesenteric lymphatics; mortality; multi-drug resistant pathogen; new therapeutic target; novel; novel therapeutic intervention; pandemic disease; pathogen; pathogenic bacteria; programs; response; secondary lymphoid organ; self-renewal; single-cell RNA sequencing; standard of care; therapeutic target; transcription factor

Abstract Spontaneous bacterial peritonitis (SBP) is a major complication of cirrhosis and associated with high mortality rate. Moreover, the effectiveness of antimicrobial therapy, the current standard of care, is deteriorating due to the global emergence of multidrug-resistant pathogens. Hence, it is essential to develop novel management strategies, for which furthering our understanding of the pathophysiology is imperative. Gut dysbiosis and impaired intestinal immunity in cirrhosis cooperatively predispose to the translocation of gut flora into the mesenteric lymphatics and, subsequently, to the peritoneum. Although this mechanism has been regarded as the primary pathophysiology, SBP develops only when the balance between peritoneal antibacterial immunity and bacterial virulence shifts in favor of the invading pathogen. Peritoneal macrophage (PM) is the major cell type in the peritoneum and is considered as the first line of antibacterial defense owing to the robust capacity in the engulfment and phagolysosomal digestion of pathogens. Moreover, PM sensing of microbe results in the production of cytokines/chemokines required for neutrophil recruitment and activation. Accordingly, PM is also essential for triggering the second wave of antibacterial response. Despite its perceived importance, the role of PM in SBP has been poorly understood. Furthermore, it remains largely elusive whether the development of cirrhosis alters the antibacterial properties of PM, and how it impacts the overall potency of peritoneal antibacterial immunity. Our single cell RNA sequencing analyses of peritoneal immune cells of rat with cirrhosis demonstrate a profound alteration of PM characteristics, including a substantial downregulation of the master regulator of PM, GATA6, a vitamin A (VA)-inducible transcription factor. In addition, PM of cirrhotic rats exhibit a markedly reduced capacity to produce inflammatory mediators in response to bacterial peritonitis, resulting in impaired neutrophil recruitment and activation as well as the insufficient bacterial clearance. Our studies also reveal that two common features of cirrhosis, VA deficiency and ascites accumulation, both independently contribute to the dysregulation of PM antibacterial function, with both processes involving GATA6 downregulation. Moreover, PM isolated from cirrhosis patients demonstrate a decreased number of GATA6-expressing PM, which correlates with the degree of antibacterial function impairment. These findings led to our hypothesis: “cirrhosis impairs the antibacterial properties of PM through the downregulation of GATA6 expression, which contributes to SBP development”. Accordingly, this proposal aims to close the knowledge gap regarding the role of PM in SBP through defining: (Aim 1) the impact of cirrhosis on PM antibacterial functions, (Aim 2) the influence of VA insufficiency on PM antibacterial properties, and (Aim 3) the effect of cirrhotic ascites on the antimicrobial activity of PM. The successful completion of the proposed studies will result in a paradigm shift in our understanding of SBP pathophysiology and ultimately define therapeutic targets for the development of novel therapeutic strategies.

抽象的 自发性细菌性腹膜炎（SBP）是肝硬化的主要并发症，与高腹膜炎相关。 此外，目前的护理标准抗菌疗法的有效性正在恶化。 由于多重耐药病原体在全球范围内的出现，因此开发新的药物至关重要。 管理策略，为此加深我们对病理生理学的理解势在必行。 肝硬化时肠道菌群失调和肠道免疫受损共同导致肠道菌群易位 肠道菌群进入肠系膜淋巴管，随后进入腹膜。 SBP被认为是主要的病理生理学，只有当腹膜之间的平衡时才会发生SBP 抗菌免疫力和细菌毒力向有利于入侵病原体的方向转变。 腹膜巨噬细胞（PM）是腹膜中的主要细胞类型，被认为是腹膜巨噬细胞的第一线。 由于吞噬和吞噬溶酶体消化病原体的强大能力而具有抗菌防御能力。 此外，微生物的 PM 感应导致中性粒细胞所需的细胞因子/趋化因子的产生 因此，PM 对于引发第二波抗菌也至关重要。 尽管 PM 在 SBP 中的作用被认为很重要，但人们对它的了解却很少。 肝硬化的发展是否会改变 PM 的抗菌特性，以及如何改变，目前仍不清楚 它影响腹膜抗菌免疫力的整体效力。 我们对肝硬化大鼠腹膜免疫细胞的单细胞 RNA 测序分析表明 PM 特性的广泛改变，包括 PM 主调节器的大幅下调， GATA6，一种维生素 A (VA) 诱导转录因子，此外，肝硬化大鼠的 PM 显着降低。 针对细菌性腹膜炎产生炎症介质的能力，导致中性粒细胞受损 我们的研究还揭示了两种常见的现象：招募和激活以及细菌清除不足。 肝硬化、VA 缺乏和腹水积聚的特征，两者独立地导致失调 PM 抗菌功能，与 GATA6 下调此外，PM 分离。 肝硬化患者表现出表达 GATA6 的 PM 数量减少，这与肝硬化程度相关 这些发现导致了我们的假设：“肝硬化会损害抗菌功能。 通过下调 GATA6 表达来调节 PM 的特性，从而有助于 SBP 的发展”。 因此，本提案旨在通过以下方式缩小关于 PM 在 SBP 中的作用的知识差距： 定义：（目标 1）肝硬化对 PM 抗菌功能的影响，（目标 2）VA 不足的影响 PM 抗菌特性的影响，以及（目标 3）肝硬化腹水对 PM 抗菌活性的影响。 拟议研究的成功完成将导致我们对 SBP 理解的范式转变 病理生理学并最终确定治疗目标以开发新的治疗策略。