Reconstructing Cell-Cell Interactions in Diverse Inflammatory Environments

重建多种炎症环境中的细胞间相互作用

• 批准号: 10797973
• 负责人: Laurel Erin Hind
• 金额: $ 25万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797973
• 关键词: 3-Dimensional; Address; Architecture; Autoimmune Diseases; Behavior; Behavior Therapy; Biology; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cell Communication; Cells; Complex; Cues; Devices; Disease; Disease Progression; Endothelial Cells; Engineering; Environment; Experimental Models; Extracellular Matrix; Extravasation; Fibrosis; Future; Goals; Homeostasis; Human; Immune; In Vitro; Individual; Infection; Inflammation; Inflammatory; Innate Immune Response; Knowledge; Laboratories; Macrophage; Malignant Neoplasms; Microfluidics; Modeling; Molecular; Neutrophil Infiltration; Pattern; Pericytes; Physiological; Play; Population; Role; Signal Transduction; Signaling Molecule; Source; Stimulus; Tissues; Work; antimicrobial; cell type; chronic infection; cytokine; design; in vitro Model; in vivo; inflammatory milieu; interest; migration; neutrophil; novel; pathogen; repaired; response; therapeutic target; wound healing

SUMMARY Neutrophils, the most abundant innate immune cell type, play a critical role in clearing infections, healing wounds, and repairing damaged tissues. Our laboratory seeks to understand how diverse inflammatory signals regulate the neutrophil response to inflammation using engineered in vitro platforms designed to mimic in vivo biology with human cells. Specifically, we are interested in determining how (i) secreted inflammatory signals, (ii) multicellular interactions, and (iii) the extracellular matrix regulate neutrophil behavior with the long-term goal of identifying targets to modulate neutrophil recruitment and function to treat infections and neutrophil-associated diseases. To properly function, neutrophils must integrate the unique set of cues released by each inflammatory environment into a specific, directed, and tightly regulated response. Defective neutrophil recruitment, excessive neutrophil infiltration, or improperly controlled neutrophil function contributes to chronic infections, tissue damage, and the progression of diseases including cancer, cardiovascular disease, autoimmune disease, and fibrosis. The individual steps of the neutrophil response (activation, extravasation, migration, and antimicrobial function) are coordinated by a wide variety of secreted proinflammatory signals released by the activated vasculature, tissue resident cells, circulating cells, and pathogens; however, the different mechanisms through which each of these soluble signals and cell populations regulate neutrophil recruitment and function are undefined. Importantly, how neutrophil behavior varies in response to differing inflammatory cues and how neutrophils integrate multiple cues into a directed response remain unanswered questions. This knowledge gap exists due to the limitations of the current experimental platforms, which fail to capture the complex milieu of signals, multicellular interactions, or three-dimensional architecture of the in vivo environment. To address this challenge, we have recently developed a novel inflammation-on-a-chip device that includes key aspects of the inflammatory environment including a model blood vessel, primary human immune cells, extracellular matrix, and a source of live pathogen or proinflammatory cytokine to investigate the primary human neutrophil response in a physiologically relevant in vitro model. Over the next five years, we will exploit the modularity of our inflammation-on-a-chip device to develop a comprehensive understanding of how individual inflammatory stimuli (pathogens, pathogen-associated molecular patterns, damage-associated molecular patterns, cytokines) and interactions with varied inflammatory cell populations (endothelial cells, pericytes, macrophages, platelets) regulate neutrophil function. We will identify key signaling molecules and signaling network hubs that broadly regulate the neutrophil response or are uniquely important for the neutrophil response to individual stimuli. This work builds toward our long-term goal of identifying therapeutic targets to control neutrophil behavior for the treatment of inflammatory diseases and will advance the study of inflammation by further developing our modular, multicellular, physiologically relevant experimental model for investigating the innate immune response.

总结 中性粒细胞是最丰富的先天免疫细胞类型，在清除感染、愈合伤口、 修复受损组织我们的实验室试图了解不同的炎症信号如何调节 使用设计用于模拟体内生物学的工程化体外平台， 人类细胞。具体来说，我们有兴趣确定（i）如何分泌炎症信号，（ii） 多细胞相互作用，和（iii）细胞外基质调节中性粒细胞的行为，长期目标是 鉴定调节中性粒细胞募集和功能以治疗感染和嗜中性粒细胞相关性 疾病为了正常发挥作用，中性粒细胞必须整合每个炎症反应释放的独特信号， 环境转化为特定的，定向的，严格调节的反应。中性粒细胞过度募集缺陷 中性粒细胞浸润或中性粒细胞功能控制不当导致慢性感染、组织炎、淋巴细胞浸润和淋巴细胞浸润。 损伤和疾病的进展，包括癌症、心血管疾病、自身免疫性疾病，以及 纤维化中性粒细胞反应的各个步骤（活化、外渗、迁移和抗菌 功能）是由多种分泌的促炎信号所协调的，这些信号是由激活的 血管系统，组织驻留细胞，循环细胞和病原体;然而，不同的机制，通过 这些可溶性信号和细胞群中的每一个调节中性粒细胞的募集和功能， 未定义。重要的是，中性粒细胞的行为如何响应不同的炎症线索而变化， 中性粒细胞将多种线索整合成定向反应仍然是未回答的问题。这一知识空白 由于目前的实验平台的局限性，无法捕捉复杂的环境， 信号、多细胞相互作用或体内环境的三维结构。为了解决这个 挑战，我们最近开发了一种新的炎症芯片设备，包括关键方面的 炎症环境，包括模型血管，原代人免疫细胞，细胞外基质， 和活病原体或促炎细胞因子的来源，以研究原发性人中性粒细胞应答 在生理学相关的体外模型中。在接下来的五年里，我们将利用我们的模块化， 炎症芯片设备，以全面了解单个炎症刺激如何 （病原体、病原体相关分子模式、损伤相关分子模式、细胞因子）和 与各种炎症细胞群（内皮细胞、周细胞、巨噬细胞、血小板）的相互作用 调节中性粒细胞功能。我们将确定关键的信号分子和信号网络枢纽， 调节嗜中性粒细胞的反应，或者对于嗜中性粒细胞对个体刺激的反应是唯一重要的。这 我们的工作朝着我们的长期目标发展，即确定治疗靶点，以控制中性粒细胞的行为， 治疗炎症性疾病，并将通过进一步开发我们的 用于研究先天免疫应答的模块化、多细胞、生理学相关实验模型。

项目成果

Diverse bacteria elicit distinct neutrophil responses in a physiologically relevant model of infection.

• DOI: 10.1016/j.isci.2023.108627
• 发表时间: 2024-01-19
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Richardson, Isaac M.;Calo, Christopher J.;Ginter, Eric L.;Niehaus, Elise;Hind, Laurel E.
• 通讯作者: Hind, Laurel E.