Neutrophil Dynamics in Nasal Mucosa

鼻粘膜中性粒细胞动态

• 批准号: 10638705
• 负责人: ULRICH H VON ANDRIAN
• 金额: $ 68.93万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-03 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638705
• 关键词: Address; Adhesions; Adoptive Transfer; Affect; Air; Anatomy; Antigen-Presenting Cells; Antigens; Bacterial Infections; Behavior; Blood; Blood Vessels; Bone Marrow; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Candida albicans; Cells; Cephalic; Characteristics; Chlamydia muridarum; Clinical; Complex; Data; Disease; Environment; Exposure to; Flow Cytometry; Gene Expression Profile; Germ-Free; Goals; Health; Homeostasis; Homing; Host Defense; Human; Hypersensitivity; ITGAX gene; Immune; Immune response; Immunobiology; Immunologic Surveillance; Immunologics; Infection; Inhalation; Innate Immune Response; Leukocytes; Mammals; Microcirculation; Microscopy; Modeling; Molecular; Morphology; Mucous Membrane; Mus; Mycoses; Nasal cavity; Neutrophil Infiltration; Nose; Organ; Parabiosis; Pathologic; Phenotype; Physiological; Play; Population; Property; Respiratory Tract Infections; Role; Sensory; Stimulus; Streptococcus pneumoniae; Structure of mucous membrane of nose; Submucosa; Surface; Surveys; T cell response; Testing; Tissues; Upper respiratory tract; Vaccines; Vertebrates; Work; adaptive immune response; conditioning; experimental study; extracellular; improved; intravital microscopy; microbial; microbiome; microorganism interaction; migration; neutrophil; novel; opportunistic pathogen; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; progenitor; recruit; respiratory pathogen; single-cell RNA sequencing; source localization; transcriptome sequencing; transcriptomics; Address; Adhesions; Adoptive Transfer; Affect; Air; Anatomy; Antigen-Presenting Cells; Antigens; Bacterial Infections; Behavior; Blood; Blood Vessels; Bone Marrow; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Candida albicans; Cells; Cephalic; Characteristics; Chlamydia muridarum; Clinical; Complex; Data; Disease; Environment; Exposure to; Flow Cytometry; Gene Expression Profile; Germ-Free; Goals; Health; Homeostasis; Homing; Host Defense; Human; Hypersensitivity; ITGAX gene; Immune; Immune response; Immunobiology; Immunologic Surveillance; Immunologics; Infection; Inhalation; Innate Immune Response; Leukocytes; Mammals; Microcirculation; Microscopy; Modeling; Molecular; Morphology; Mucous Membrane; Mus; Mycoses; Nasal cavity; Neutrophil Infiltration; Nose; Organ; Parabiosis; Pathologic; Phenotype; Physiological; Play; Population; Property; Respiratory Tract Infections; Role; Sensory; Stimulus; Streptococcus pneumoniae; Structure of mucous membrane of nose; Submucosa; Surface; Surveys; T cell response; Testing; Tissues; Upper respiratory tract; Vaccines; Vertebrates; Work; adaptive immune response; conditioning; experimental study; extracellular; improved; intravital microscopy; microbial; microbiome; microorganism interaction; migration; neutrophil; novel; opportunistic pathogen; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; progenitor; recruit; respiratory pathogen; single-cell RNA sequencing; source localization; transcriptome sequencing; transcriptomics

The nasal mucosa (NM) has several critical physiologic functions, including as a chemosensory organ, as a filter and conditioning surface of inhaled air for the lower airways, and as a first line of defense against airborne infections. In mammals, the nasal passage is anatomically complex, with different sub-compartments with distinct morphological and cellular features that may exert specialized, but as yet poorly understood, functions. Owing to its constant exposure to ever-changing environments, the NM is arguably the most frequently infected tissue in mammals. Aside from being a preferred initial target for many fungal, viral and bacterial pathogens, some of which may subsequently spread to the lower airways, blood, brain or other cranial regions, the nasal cavity is also colonized by a specialized microbiome that can serve as a reservoir for opportunistic pathogens. Despite the NM's importance for human health, little is known about the mechanisms by which local immune responses are initiated and/or regulated. Arguably, the NM must possess specialized features to enable appropriate innate and adaptive immune responses against a broad variety of challenges. The NM is known to harbor a population of subepithelial extravascular immune cells, but their origin, composition, and role at steady-state and in pathologic conditions are poorly understood. To address this issue, a novel intravital microscopy (IVM) model was devised to track the dynamic behavior of leukocytes in the NM of living mice. Preliminary results indicate that murine steady-state NM harbors a prominent population of extravascular neutrophils (EVN) that are abundant in both conventional and germ-free mice, suggesting that their presence is not driven by microbial stimuli. Furthermore, nasal EVN can be subdivided into three phenotypically distinct subsets: one population (termed N1) is CD11bint Ly6Gint, while the other two subsets are both CD11bhi Ly6Ghi and distinguishable by the absence (N2) or presence (N3) of CD11c and SiglecF. The primary objective of this project is to define how these unusual EVN subsets arise, how they respond to infectious challenges and what role they play in health and disease. It is hypothesized that each nasal EVN subset has a distinct origin, accesses the NM by discrete mechanisms, and exerts specialized functions in tissue homeostasis and in host defense against microbial infections. To test this hypothesis, Aim 1 will explore the origin and migratory properties of steady-state nasal EVN subsets, whereas Aim 2 will define the function of each EVN subset in homeostasis and after intranasal pathogen challenge. Results from the proposed work may not only improve our understanding of the NM as a critical barrier tissue, but also shed new light on immunological mechanisms that may impact the efficacy of nasal vaccines and on pathologic conditions affecting the nasal cavity such as allergies and a host of respiratory infections.

鼻粘膜（NM）具有多种关键的生理功能，包括作为化学体器官，作为下气道的吸入空气的过滤器和调节表面，以及针对机载感染的第一道防线。在哺乳动物中，鼻腔段落在解剖学上是复杂的，具有不同的子室具有不同的形态和细胞特征，可能会发挥专门功能，但尚未理解的功能。由于它不断暴露于不断变化的环境，NM可以说是哺乳动物中最常见的组织。除了是许多真菌，病毒和细菌病原体的首选初始靶标，其中一些可能随后扩展到下部气道，血液，脑或其他颅区域外，还通过专门的微生物组殖民了鼻腔，可以用作机会性病原体的储量。尽管NM对人类健康的重要性，但对启动和/或调节局部免疫反应的机制知之甚少。可以说，NM必须具有专门的特征，以使适当的先天和适应性免疫反应应对各种各样的挑战。已知NM具有上皮下血管外免疫细胞的群体，但其起源，组成和在稳态和病理条件下的作用知之甚少。为了解决这个问题，设计了一种新型的插入式显微镜（IVM）模型，以跟踪活小鼠NM中白细胞的动态行为。初步结果表明，鼠稳态NM具有突出的血管外嗜中性粒细胞（EVN），它们在常规和无菌小鼠中都很丰富，这表明它们的存在不是由微生物刺激驱动的。此外，可以将鼻EVN细分为三种表型不同的子集：一个人群（称为N1）是CD11BINT LY6GINT，而其他两个子集都是CD11bhi Ly6GHi，并且可以通过CD11C和SigleCF的缺失（N2）或（N2）或（N3）或SIGLECF进行区分。该项目的主要目的是定义这些不寻常的EVN子集如何出现，它们如何应对感染挑战以及它们在健康和疾病中的作用。假设每个鼻腔EVN子集具有独特的起源，可以通过离散机制访问NM，并在组织稳态中发挥专门功能，并在宿主防御微生物感染中发挥了防御性。为了检验这一假设，AIM 1将探讨稳态鼻EVN子集的起源和迁移特性，而AIM 2将定义每个EVN子集在稳态中和鼻内病原体挑战之后的功能。提议的工作的结果不仅可以改善我们对NM作为关键屏障组织的理解，而且还为可能影响鼻腔疫苗的功效和影响鼻腔（例如过敏和呼吸道感染的宿主）的病理状况的免疫机制提供了新的启示。