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Mechanisms of lung macrophage programming by MUC5B during health and disease

MUC5B 在健康和疾病期间对肺巨噬细胞编程的机制

基本信息

批准号：
9750783
负责人：
Christopher M Evans
金额：
$ 63.88万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2022-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750783
关键词：
Acute Alveolar Macrophages Apoptosis Attenuated Back Bacteria Binding Biological Assay Coughing Dependence Deposition Development Disease Down-Regulation Exposure to Genetically Engineered Mouse Glycoconjugates Health Homeostasis Host Defense Immunoglobulins Immunologics Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Ingestion Inhalation Injury Knock-out Knockout Mice Laboratories Lectin Receptors Ligands Link Lung MUC5B gene Measurement Mediating Modeling Molecular Mucins Mucociliary Clearance Mucous body substance Mus Physiological Pneumonia Polysaccharides Prevention Production RNA Interference Regulation Resolution Rest Role Sialic Acids Signal Transduction Staphylococcus aureus Stimulus Testing Time glycosylation in vivo inflammatory lung disease macrophage monocyte novel particle pathogen programs recruit restoration selective expression sialic acid binding Ig-like lectin

项目摘要

PROJECT SUMMARY Each day, the lungs are exposed to billions of particles whose accumulation can potentially cause infection and damage. While it is crucial to defend against these exposures, it is equally important that protection occurs with minimal physiological disruption or injury caused by inflammation. Mucus and macrophage clearance are hallmark non-inflammatory defenses. Particles and pathogens that deposit in the airways are trapped in mucus and eliminated by ciliary and cough forces, while those in alveoli are ingested by alveolar macrophages (AMs). Using Muc5b knockout mice, we previously showed that Muc5b is required for effective mucociliary clearance and for maintaining healthy pools of resident AMs. The primary objective of this proposal is to determine specific mechanisms by which Muc5b regulates AM function during homeostasis and during acute and resolving inflammation. We have identified a novel mechanism that directly links Muc5b to AM function via sialic acid-binding immunoglobulin-type lectin receptor-F (Siglec-F), an inhibitory immunoreceptor that is expressed selectively by resident AMs and is known to bind α2,3-linked sialic acid-containing glycoconjugates. Muc5b is α2,3-sialylated and is an endogenous Siglec-F ligand. We propose that stimulation of Siglec-F by Muc5b calibrates AM inflammatory responses in the resting lung. Thus, in healthy states, the ability of resident AMs to serve protective roles while simultaneously limiting potentially injurious inflammatory responses may occur by a homeostatic programming mechanism mediated by stimulation of Siglec-F by Muc5b. When homeostasis is disrupted by stimuli such as bacteria, a temporary induction of AM inflammatory responsiveness is required. Furthermore, resident AMs are joined by recruited macrophages that arise from circulating monocytes. These recruited monocyte-derived AMs (MDAMs) lack Siglec-F and are highly pro- inflammatory. At the same time that MDAMs are recruited, resident AMs down-regulate their Siglec-F expression and become pro-inflammatory. As inflammation resolves, recruited MDAMs undergo apoptosis and are eliminated, whereas resident AMs restore Siglec-F expression and return to their non-inflammatory states. We postulate that transient reduction of MUC5B:Siglec-F signaling permits an inflammatory response and that restoration of MUC5B:Siglec F signaling is required for its resolution. We hypothesize that stimulation of Siglec-F by Muc5b is a major mechanism for controlling macrophage inflammatory responses during homeostasis and inflammation. We will use wild type and genetically engineered mice, models of acute inflammation, and immunological readouts to test this hypothesis in the following three Specific Aims: 1. Test the hypothesis that during homeostasis, protective AM activities are maintained by MUC5B sialyl glycan- dependent Siglec-F stimulation. 2. Test the hypothesis that MUC5B:Siglec-F dependent inhibitory mechanisms are lost during acute inflammation. 3. Test the hypothesis that re-engagement of MUC5B with Siglec-F on AMs drives the resolution of inflammation.

项目总结