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: 10816167
• 负责人: Rachel A Gottschalk
• 金额: $ 7.61万
• 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/10816167
• 关键词: Alveolar Macrophages; Anti-Inflammatory Agents; Bacterial Pneumonia; Cells; Cytokine Signaling; Disease; Equilibrium; Event; Family; Goals; Health; Homeostasis; Immune; Immunosuppression; Impairment; Infection; Inflammatory; Inflammatory Response; Link; Lipids; Lung; Lung diseases; Lung infections; Macrophage; Metabolism; Morbidity - disease rate; Phenotype; Phosphotransferases; Predisposition; Process; Pulmonary Surfactants; Research; Resolution; Role; Shapes; Signal Transduction; Stimulus; Therapeutic; Tissues; Work; cytokine; functional plasticity; immune function; insight; lipid metabolism; microbial; mortality; pathogen; programs; response

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.

摘要 肺泡巨噬细胞(AM)处理富含脂质的肺表面活性物质，并具有稳定的免疫抑制作用 支持肺部动态平衡的功能。在感染期间，AM可以迅速从抗炎转变为促炎 支持病原体清除的炎症计划。AM反式和亲式AM平衡失调 炎症反应导致细菌性肺炎死亡率增加。虽然大家都很理解， 肺微环境塑造组织特异性AM功能，对持续信号知之甚少 在健康和疾病中对AM进行编程的事件，这限制了我们从治疗上操纵AM的能力。我们 证明在SOCS家族中的负调控因子CisH在AM中有结构性的表达。CISH缺陷的AMS 有富含脂质的泡沫表型，GATA2活性增加，炎症反应减弱 微生物刺激。这项提议的中心是定义将肺部特异性刺激联系起来的信号机制 对巨噬细胞功能的影响，重点了解CISH-GATA2调节节点在AM中的作用 编程、肺部动态平衡和细菌性肺炎。我们的中心假设是肺细胞因子 增强GATA2活性以促进AM脂代谢和抗炎功能 抑制这些过程，以支持感染反应的功能可塑性。在目标1中，我们将 确定特定的稳态细胞因子和相关的激酶编程AM的机制 新陈代谢和炎症反应。在目标2中，我们将定义CISH-GATA2监管的作用 结节在控制AM促炎和抗炎功能的过程中细菌肺部感染和消退。这部作品 意义重大，因为它将提供对作为AM编程基础的信令过程的机械性洞察， 与肺部感染相关的肺内稳态和发病率的一个明显重要的方面。