Role of AC7 and alcohol in innate immune responses during bacterial infection

AC7 和酒精在细菌感染期间先天免疫反应中的作用

基本信息

批准号：
10494203
负责人：
Masami Yoshimura
金额：
$ 7.26万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10494203
关键词：
Acute Adenosine Adenylate Cyclase Aftercare Agonist Alcohol consumption Alcohols Alveolar Macrophages Animal Model Animals Autoimmune Diseases Bacteria Bacterial Infections Blood Circulation Bronchoalveolar Lavage Fluid Cells Chronic Disease Coupled Cyclic AMP Data Dinoprostone Disease Epinephrine Escherichia coli Ethanol Foundations GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Generations Goals Health Human Immune Immune response Immune system Immunoassay Immunosuppression In Vitro Incidence Infection Infiltration Inflammatory Injections Injury Innate Immune Response Intervention Intraperitoneal Injections Knock-out Knockout Mice Lead Lung Mediating Messenger RNA Myelogenous Myeloid Cells Natural Immunity Nerve Degeneration Oral Peritoneal Phagocytosis Pharmaceutical Preparations Pharmacology Plasma Play Protein Isoforms Pulmonary Inflammation Recovery Research Reverse Transcriptase Polymerase Chain Reaction Risk Role Structure of parenchyma of lung System Systems Analysis Therapeutic Intervention Tissues Traumatic injury Virus adaptive immunity alcohol consequences alcohol effect base chemokine chronic alcohol ingestion cytokine economic cost human model mouse model negative affect neuroinflammation receptor response sepsis induced acute lung injury socioeconomics

项目摘要

Project Summary/Abstract Alcohol consumption compromises the function of various components of the immune defense system by modulating innate and adaptive immunity in both humans and animal models. However, the mechanisms responsible for ethanol’s effects on the immune system are not fully understood. It is well established that cyclic AMP (cAMP) regulates immune responses; however, whether a specific adenylyl cyclase (AC) isoform is primarily responsible for mediating on ethanol’s effects on immune responses has not yet been clearly determined. Our long-term goal is to elucidate a) which specific isoform(s) of AC modulate(s) ethanol’s effects on immune responses, and b) the mechanisms underlying this modulation. Using myeloid lineage specific type 7 AC isoform (AC7) knockout mice, our preliminary data indicate that the suppressive effect of acute ethanol ingestion on cytokine expression in the lung requires AC7 expression in myeloid cells. Thus, we hypothesize that AC7 plays a key role in regulating the effects of acute alcohol ingestion on the immune system. We postulate that acute ingestion of alcohol results in an increase in one or more Gs-coupled receptor agonist(s) either locally in the lung or systemically in circulation. This, in turn, stimulates AC7 activity in myeloid cells, such as alveolar macrophages, resulting in suppression of immune responses. In this proposal, we will utilize the myeloid lineage specific AC7 knockout mice. We will employ acute alcohol ingestion combined with live bacteria peritoneal injection to elucidate the mechanisms by which ethanol suppresses innate immune responses via AC7 activity. This is a well-established mouse model for acute lung injury induced by sepsis in humans. The Specific Aims of the proposal are Aim 1: To determine innate immune responses in the lung of the myeloid lineage specific AC7 knockout mice in response to bacterial infection and acute ethanol treatment and Aim 2: To quantify Gs-coupled receptor agonists in bronchoalveolar lavage fluid and plasma and cAMP levels in the lungs of animals treated with alcohol and live bacteria. We postulate that adenosine, adrenaline, and prostaglandin E2 are the prime candidates for Gs-coupled receptor agonists increasing by acute ethanol ingestion. The proposed study is concise and focused on acute alcohol effects on lung inflammation caused by bacterial infection. Results from the proposed studies will generate mechanistic information regarding the effects of alcohol on the immune system via AC7 activity. The data derived from this study will become a foundation for future research in which mechanistic aspects of alcohol effects on immune system are studied in detail and may lead to a pharmacological intervention to counter negative consequences of alcohol ingestion.

项目概要/摘要饮酒会损害免疫防御系统各个组成部分的功能然而，在人类和动物模型中调节先天性和适应性免疫。众所周知，乙醇对免疫系统的影响尚未完全明确。 AMP (cAMP) 调节免疫反应；然而，特定的腺苷酸环化酶 (AC) 亚型是否主要负责介导乙醇对免疫反应的影响尚未明确我们的长期目标是阐明 a) AC 的哪种特定异构体可调节乙醇。对免疫反应的影响，以及 b) 这种调节的机制。使用骨髓谱系特异性 7 型 AC 亚型 (AC7) 敲除小鼠，我们的初步数据表明急性乙醇摄入对肺部细胞因子表达的抑制作用需要 AC7 表达因此，我们认为 AC7 在调节急性酒精的影响中发挥着关键作用。我们假设急性摄入酒精会导致一种或几种的增加。更多的 Gs 偶联受体激动剂要么局部存在于肺部，要么全身循环。刺激骨髓细胞（例如肺泡巨噬细胞）中的 AC7 活性，从而抑制免疫在本提案中，我们将利用骨髓谱系特异性 AC7 敲除小鼠。酒精摄入结合活菌腹腔注射，阐明乙醇的作用机制通过 AC7 活性抑制先天免疫反应这是一个成熟的急性肺小鼠模型。该提案的具体目标是目标 1：确定先天免疫。骨髓谱系特异性 AC7 敲除小鼠肺部对细菌的反应感染和急性乙醇治疗以及目标 2：量化 Gs 偶联受体激动剂用酒精处理的动物的支气管肺泡灌洗液以及血浆和肺部 cAMP 水平我们假设腺苷、肾上腺素和前列腺素 E2 是主要候选物。急性乙醇摄入会增加 Gs 偶联受体激动剂的浓度。这项研究简洁而重点突出。拟议研究的结果对酒精对细菌感染引起的肺部炎症的影响。将通过 AC7 活性生成有关酒精对免疫系统影响的机制信息。从这项研究中获得的数据将成为未来研究的基础，其中机械方面酒精对免疫系统的影响已得到详细研究，并可能导致药物干预来对抗摄入酒精的负面后果。