Ion Flux Regulation of Macrophage Plasticity in Lung Injury and Repair

肺损伤与修复中巨噬细胞可塑性的离子通量调节

• 批准号: 10170863
• 负责人: Asrar B. Malik
• 金额: $ 42.55万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10170863
• 关键词: Abbreviations; Address; Anti-Inflammatory Agents; CREB1 gene; Cells; Collaborations; Cyclic AMP-Responsive DNA-Binding Protein; Data; Electrophysiology (science); Gene Deletion; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Ion Channel; Ions; Lead; Left; Ligands; Lung; Mediating; Metabolic; Microbe; Modeling; Oncogenes; Pathway interactions; Patients; Phenotype; Potassium; Potassium Channel; Purinoceptor; Regulation; Resolution; Role; Rous Sarcoma; SRC gene; STAT1 gene; STAT1 protein; STAT6 Transcription Factor; STAT6 gene; Signal Pathway; Signal Transduction; Testing; Tissues; Transcriptional Activation; base; calmodulin-dependent protein kinase II; extracellular; injury and repair; innate immune function; inward rectifier potassium channel; lung injury; lung repair; macrophage; novel; optogenetics; programs; pulmonary function; response; success; transcription factor

PROJECT SUMMARY/ABSTRACT Macrophages (Mφ) are essential for the innate immune function of lungs. The ability of macrophages to integrate signals from microbes and the tissue niche and to polarize can either promote or resolve inflammatory lung injury. Project 1 shows a fundamental role of the extracellular ATP (e[ATP]) activated- and [Ca2+]in-sensitive cooperation between the purinergic receptor P2RX7 (Purinergic Receptor 2 subtype X7) and potassium (K+) channel TWIK2 (Two-pore domain Weak Inwardly rectifying K+ channel 2) that is essential for determining the macrophage phenotype. We show that e[ATP], the canonical P2RX7 ligand, governs Mφ polarization through controlling [Ca2+]in and that activation of the TWIK2 K+ efflux channel induces the transition to the pro-inflammatory state. We also observed that the TWIK2 response was itself dependent on the activation of P2RX7 by e[ATP] and resultant Ca2+ influx. Thus, Project 1, we will investigate the interactions between Ca2+ influx mediated by P2RX7 and its tuning of K+ efflux mediated by TWIK2, which we hypothesize determines the transition to either pro-inflammatory Mφ (Inf-Mφ) or reparative Mφ (Rep-Mφ) fate via activation of distinct downstream signaling pathways. This hypothesis will be tested by addressing the following Specific Aims. Aim 1 will define respective mechanisms of P2RX7 and TWIK2 activation in mediating the shift in lung macrophage polarity. Aim 2 will define the signaling pathways downstream of Mφ ion channels that promote and resolve inflammatory lung injury. We posit that by identifying P2RX7 and TWIK2 activation and signaling mechanisms responsible for macrophage phenotype switching, and by testing the role of P2RX7 in coordinating the function of TWIK2 in the initial inflammatory response followed subsequent anti-inflammatory response in Project 1, it will be possible to develop strategies to more effectively resolve inflammatory lung injury and to make lung’s tolerance to injury through controlling macrophage polarization enhancing bacterial killing function of MФ.

项目概要/摘要 巨噬细胞 (Mφ) 对于肺部的先天免疫功能至关重要。 整合来自微生物和组织生态位的信号并极化可以促进或解决 项目 1 显示了细胞外 ATP (e[ATP]) 激活和的基本作用。 [Ca2+] 嘌呤能受体 P2RX7（嘌呤能受体 2 亚型 X7）与 钾 (K+) 通道 TWIK2（双孔域弱内向整流 K+ 通道 2），对于 确定巨噬细胞表型 我们发现 e[ATP]（典型的 P2RX7 配体）控制着 Mφ。 通过控制 [Ca2+]in 极化，并且 TWIK2 K+ 外排通道的激活诱导转变 我们还观察到 TWIK2 反应本身取决于 e[ATP] 激活 P2RX7 和由此产生的 Ca2+ 流入 因此，在项目 1 中，我们将研究相互作用。 P2RX7 介导的 Ca2+ 流入与 TWIK2 介导的 K+ 流出调节之间的关系，我们 通过激活决定向促炎性 Mφ (Inf-Mφ) 或修复性 Mφ (Rep-Mφ) 命运的转变 该假设将通过解决以下具体问题进行检验。 目标 1 将定义 P2RX7 和 TWIK2 激活介导肺转移的各自机制。 目标 2 将定义促进 Mφ 离子通道下游的信号传导。 我们假设通过识别 P2RX7 和 TWIK2 激活和信号传导来解决炎症性肺损伤。 负责巨噬细胞表型转换的机制，并通过测试 P2RX7 在 协调 TWIK2 在初始炎症反应和后续抗炎反应中的功能 根据项目 1 的响应，将有可能制定更有效地解决肺部炎症的策略 损伤并通过控制巨噬细胞极化增强细菌使肺对损伤产生耐受性 MФ的杀伤功能。