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: 10701929
• 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/10701929
• 关键词: Abbreviations; Address; Anti-Inflammatory Agents; CREB1 gene; Cells; Collaborations; Cyclic AMP-Responsive DNA-Binding Protein; Data; Electrophysiology (science); Gene Deletion; Heterogeneity; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Ion Channel; Ions; Lead; Left; Ligands; Lung; Macrophage; 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; calmodulin-dependent protein kinase II; extracellular; innate immune function; inward rectifier potassium channel; lung injury; lung repair; meter; 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.

项目摘要/摘要 巨噬细胞（Mφ）对于肺的先天免疫功能至关重要。巨噬细胞的能力 来自微生物和组织生态位和极化的集成信号可以促进或解决 炎症性肺损伤。项目1显示了细胞外ATP（E [ATP]）激活的基本作用 [Ca2+]嘌呤能受体P2RX7（嘌呤能受体2亚型X7）和 钾（K+）通道Twik2（两孔域弱内向校正K+通道2），这对于对 确定巨噬细胞表型。我们表明，e [ATP]，规范P2RX7配体，控制Mφ 通过控制[Ca2+]的极化和TWIK2 K+外排信道的激活诱导过渡 到促炎性状态。我们还观察到TWIK2响应本身取决于 E [ATP]和由此产生的Ca2+影响激活P2RX7。那就是项目1，我们将研究互动 在由P2RX7介导的Ca2+影响之间，其对TWIK2介导的K+外排的调整，我们假设 通过激活确定向促炎性Mφ（INF-Mφ）或修复Mφ（Rep-Mφ）命运的过渡 独特的下游信号通路。该假设将通过解决以下特定来检验 目标。 AIM 1将定义P2RX7和TWIK2激活的相对机制，以介导肺的转移 巨噬细胞极性。 AIM 2将定义促进Mφ离子通道下游的信号通路 并解决炎症性肺损伤。我们指出，通过识别P2RX7和TWIK2激活和信号传导 负责巨噬细胞表型切换的机制，并通过测试P2RX7在 协调TWIK2在最初的炎症反应中的功能随后抗炎后 在项目1中的响应中，有可能制定策略以更有效地解决炎症肺 通过控制巨噬细胞极化来增强细菌的损伤和使肺对损伤的耐受性 杀死功能。