Characterization of the molecular mechanisms of LC3-associated phagocytosis and its role in disease pathogenesis

LC3相关吞噬作用的分子机制及其在疾病发病机制中的作用的表征

• 批准号: 9143522
• 负责人: Jennifer Martinez
• 金额: $ 58.57万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9143522
• 关键词: Accounting; Adult; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Area; Aspergillus fumigatus; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autophagocytosis; Biological Models; Cell Maintenance; Cells; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Cysteine; Defect; Development; Disease; Disease Progression; Disease model; Eating; Environment; Event; Excision; Gene Targeting; Homeostasis; Host Defense; Host Defense Mechanism; Housekeeping; Immune response; Immune system; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Invaded; Investigation; Light; Link; Longevity; Mediating; Molecular; Mus; Occupations; Organism; Outcome; Pathogenesis; Pathology; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Physiological; Play; Process; Program Research Project Grants; Proteins; Quality Control; Receptor Signaling; Recruitment Activity; Regulation; Role; Shapes; Signal Transduction; Stress; Surface; System; TLR1 gene; TLR2 gene; TLR4 gene; Technology; Tertiary Protein Structure; Time; Work; cellular development; design; extracellular; in vivo; insight; interest; macrophage; member; mouse model; pathogen; programs; receptor; response; tool

Phagocytes of the innate immune system act as surveyors of their surroundings environment, patrolling the body for unwanted, unneeded, and unexpected components and eliminating them efficiently. While clearance of invading pathogens is a common and necessary function of phagocytes, the sensing, recognition, and removal of cellular corpses, a process termed efferocytosis, is also a critical role that phagocytes play during times of development, cellular homeostasis, and stress. Considering the average 50 billion adult human cells that undergo apoptosis daily and the rarity of observing an uncleared apoptotic cells under normal physiological conditions, one must truly appreciate the magnitude of the job facing phagocytes. Moreover, as this is a reoccurring and normal event in the lifespan of an organism, this process of efferocytosis must occur in a immunologically silent manner, so as to not inappropriately alert the immune system. Therefore, the response of a phagocyte must be tailored to both the cargo and the preferred outcome. The effective clearance of extracellular components (be it pathogens or dying cells) requires that phagocytes first recognize and engulf them using surface receptors, followed by processing of the cargo and orchestration of the appropriate local and systemic immune responses. The clearance of dead cells, however, is designed to be a tolerated mechanism, as cellular death is a normal, genetically programmed process designed to sculpt, control, and aid the body in its development and survival. The tightly orchestrated process of efferocytosis can be broadly organized in 4 steps: 1) the recruitment of phagocytes by find-me signals generated by dying cells, 2) the recognition and engagement of eat-me signals by receptors or bridging molecules from phagocytes, 3) the engulfment of the cellular corpse by phagocytes, and 4) the processing, degradation, and immune response to the engulfed corpse. While much work has been accomplished to characterize the molecules responsible for attracting the phagocyte and facilitating the physical engulfment, the mechanisms by which a phagocyte handles the ingested corpse in terms of its processing, degradation, and subsequent influence on the pursuant immune response is an area of growing interest. Recent studies have identified a unique process that is critical for the clearance of both pathogens and dying cells, as well as directing the subsequent immune response to each engulfed cargo. LC3-associated phagocytosis (or LAP) is a recently discovered pathway wherein a specific signaling event is sensed during phagocytosis and recruits some, but not all, members of the autophagy machinery to the phagosome. It is the activity of these autophagic players that facilitates the rapid destruction or processing of the cargo via fusion with the lysosomal pathway. Engagement of multiple types of receptors, including TLR1/2, TLR2/6, TLR4, FcR, and TIM4 has been shown to trigger LAP to form the single-membraned, cargo-containing phagosome, termed the LAPosome. LAP is a process that marries the evolutionarily conserved pathways of phagocytosis and autophagy and allows us to reimagine the impact of the autophagy machinery on innate host defense mechanisms. This paradigm-shifting realization expands the autophagy machinerys implications beyond intracellular housekeeping to host defense against extracellular threats and sheds new light on inflammation and autoimmunity.

先天免疫系统的吞噬细胞充当其周围环境的监视器，巡逻身体以寻找不需要的、不需要的和意外的成分，并有效地消除它们。虽然入侵病原体的清除是吞噬细胞的常见和必要的功能，但细胞尸体的感知，识别和清除（称为吞噬作用的过程）也是吞噬细胞在发育，细胞稳态和应激期间发挥的关键作用。考虑到平均每天有500亿个成年人细胞经历凋亡，以及在正常生理条件下观察到未清除的凋亡细胞的罕见性，人们必须真正认识到吞噬细胞所面临的工作的重要性。此外，由于这是生物体生命周期中重复发生的正常事件，因此这种红细胞增多症的过程必须以免疫学沉默的方式发生，以免不适当地警告免疫系统。 因此，吞噬细胞的反应必须针对货物和优选的结果。有效清除细胞外成分（无论是病原体还是垂死细胞）需要吞噬细胞首先使用表面受体识别并吞噬它们，然后处理货物并协调适当的局部和全身免疫反应。 然而，死亡细胞的清除被设计为一种耐受机制，因为细胞死亡是一种正常的、遗传编程的过程，旨在塑造、控制和帮助身体发育和生存。 吞噬作用的紧密协调过程可以大致分为4个步骤：1）死亡细胞产生的find-me信号招募吞噬细胞，2）吞噬细胞的受体或桥接分子识别和参与eat-me信号，3）吞噬细胞吞噬细胞尸体，以及4）对吞噬尸体的处理，降解和免疫反应。 虽然已经完成了大量的工作来表征负责吸引吞噬细胞和促进物理吞噬的分子，吞噬细胞处理摄入的尸体的加工，降解和随后对免疫反应的影响的机制是一个越来越感兴趣的领域。 最近的研究已经确定了一个独特的过程，这对于清除病原体和垂死细胞以及引导随后的免疫反应到每个被吞噬的货物至关重要。LC 3相关的吞噬作用（或吞噬）是最近发现的途径，其中在吞噬作用期间感知特定的信号传导事件，并将自噬机制的一些但不是全部成员招募到吞噬体。 正是这些自噬参与者的活性通过与溶酶体途径融合促进了货物的快速破坏或加工。多种类型的受体，包括TLR 1/2、TLR 2/6、TLR 4、FcR和TIM 4的结合已经显示出触发噬菌体形成单膜的、含货物的吞噬体，称为LAPosome。自噬是一个结合了吞噬和自噬的进化保守途径的过程，并允许我们重新想象自噬机制对先天宿主防御机制的影响。 这种范式转变的实现将自噬机制的意义扩展到细胞内管家之外，以宿主防御细胞外威胁，并为炎症和自身免疫提供了新的见解。