Linking steady-state cytokine signaling to alveolar macrophage function in homeostasis and lung infection

将稳态细胞因子信号传导与体内平衡和肺部感染中的肺泡巨噬细胞功能联系起来

• 批准号: 10414842
• 负责人: Rachel A Gottschalk
• 金额: $ 58.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-25 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414842
• 关键词: Acute; Alveolar Macrophages; Anti-Inflammatory Agents; Bacterial Infections; Bacterial Pneumonia; Bone Marrow; Cells; Chronic lung disease; Cytokine Signaling; Development; Disease; Equilibrium; Event; Family; Gases; Genes; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Homeostasis; Human; Immune; Immune response; Immunosuppression; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Insulin-Like Growth Factor I; Lead; Link; Lipids; Lung; Lung infections; MAP Kinase Gene; Metabolic; Metabolism; Minor; Modeling; Morbidity - disease rate; Mus; Mutation; PPAR gamma; Pathology; Pharmacology; Phenotype; Phosphotransferases; Post-Translational Protein Processing; Predisposition; Process; Proteins; Proto-Oncogene Proteins c-akt; Pseudomonas aeruginosa; Pulmonary Alveolar Proteinosis; Pulmonary Surfactants; Recurrence; Resolution; Respiration; Role; Science; Shapes; Signal Pathway; Signal Transduction; Staphylococcus aureus; Stimulus; Structure of parenchyma of lung; Therapeutic; Tissues; Upper Respiratory Infections; Variant; Work; cell type; chronic inflammatory lung disease; cytokine; functional plasticity; immune function; insight; knock-down; lipid metabolism; macrophage; microbial; mortality; pathogen; preference; programs; response; transcription factor; transcriptome sequencing

SUMMARY Alveolar macrophages (AMs) process lipid-rich pulmonary surfactant and have steady-state immunosuppressive functions that support lung homeostasis. During infection, AMs can rapidly shift from anti-inflammatory to pro- inflammatory programs to support pathogen clearance. Dysregulation in the balance of AM anti- and pro- inflammatory responses leads to increased mortality in bacterial pneumonia. While it is well appreciated that the lung microenvironment shapes tissue-specific AM function, very little is known about the persistent signaling events that program AMs in health and disease, which limits our ability to manipulate AMs therapeutically. We show that Cish, a negative regulator in the SOCS family, is constitutively expressed in AMs. Cish deficient AMs have a lipid-laden foamy phenotype, increased GATA2 activity, and impaired inflammatory responses to microbial stimuli. This proposal is centered around defining signaling mechanisms that link lung-specific stimuli to macrophage function, with a focus on understanding the role of the CISH-GATA2 regulatory node in AM programming, lung homeostasis, and bacterial pneumonia. Our central hypothesis is that lung cytokines drive GATA2 activity to promote AM lipid metabolism and anti-inflammatory function, and that CISH inhibits these processes to support functional plasticity in response to infection. In Aim 1, we will determine mechanisms by which specific steady-state cytokines and associated kinases program AM metabolism and inflammatory responsiveness. In Aim 2, we will define the role of the CISH-GATA2 regulatory node in control of AM pro- and anti-inflammatory function during bacterial lung infection and resolution. This work is significant because it will provide mechanistic insight into signaling processes that underlie AM programming, a clearly important aspect of lung homeostasis and morbidity associated with pulmonary infection.

概括 肺泡巨噬细胞（AM）处理富含脂质的肺表面活性物质并具有稳态免疫抑制作用 支持肺稳态的功能。在感染过程中，AMs 可以迅速从抗炎作用转变为促炎作用。 支持病原体清除的炎症程序。 AM 抗和亲平衡失调 炎症反应导致细菌性肺炎死亡率增加。尽管人们普遍赞赏 肺微环境塑造组织特异性 AM 功能，但对持续信号传导知之甚少 在健康和疾病中对 AM 进行编程的事件，这限制了我们在治疗上操纵 AM 的能力。我们 表明 Cish 是 SOCS 家族中的负调节因子，在 AM 中组成型表达。 Cish 缺陷 AM 具有富含脂质的泡沫表型、GATA2 活性增加以及炎症反应受损 微生物刺激。该提案的重点是定义连接肺部特定刺激的信号机制 巨噬细胞功能，重点了解 CISH-GATA2 调节节点在 AM 中的作用 编程、肺稳态和细菌性肺炎。我们的中心假设是肺细胞因子 驱动GATA2活性促进AM脂质代谢和抗炎功能，并且CISH 抑制这些过程以支持响应感染的功能可塑性。在目标 1 中，我们将 确定特定稳态细胞因子和相关激酶程序 AM 的机制 代谢和炎症反应。在目标 2 中，我们将定义 CISH-GATA2 监管的作用 在细菌性肺部感染和消退过程中控制 AM 促炎和抗炎功能的节点。这部作品 很重要，因为它将提供对 AM 编程基础的信号处理过程的机械洞察， 肺稳态和与肺部感染相关的发病率的一个明显重要方面。