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.

总结 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。 支持肺内环境稳定的功能。在感染过程中，AM可以迅速从抗炎转变为促炎。 炎症程序以支持病原体清除。AM抗-和亲-的平衡失调 炎症反应导致细菌性肺炎死亡率增加。虽然很好地理解， 肺微环境塑造了组织特异性AM功能，关于持续的信号传导知之甚少。 在健康和疾病中编程AM的事件，这限制了我们在治疗上操纵AM的能力。我们 显示Cish，SOCS家族中负调节因子，在AM中组成型表达。Cish缺陷型AM 具有脂质填充泡沫表型、增加的GATA 2活性和受损的炎症反应， 微生物刺激这个提议的核心是定义连接肺部特异性刺激的信号机制 巨噬细胞功能，重点是了解CISH-GATA 2调节节点在AM中的作用 编程、肺内稳态和细菌性肺炎。我们的中心假设是肺细胞因子 驱动GATA 2活性，促进AM脂质代谢和抗炎作用，CISH 抑制这些过程以支持对感染做出反应的功能可塑性。在目标1中，我们 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-GATA 2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。这项工作 是重要的，因为它将提供对作为AM编程基础的信号过程的机械洞察， 肺内环境稳定和与肺部感染相关的发病率的一个明显重要的方面。