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

先天免疫系统的吞噬细胞充当周围环境的监测器，在体内巡逻，寻找不需要的、不需要的和意想不到的成分，并有效地将它们清除。虽然清除入侵的病原体是吞噬细胞常见和必要的功能，但吞噬细胞的感知、识别和清除身体的过程称为胞吐作用，也是吞噬细胞在发育、细胞动态平衡和应激过程中发挥的关键作用。考虑到平均每天有500亿成人细胞发生凋亡，以及在正常生理条件下观察到未清除的凋亡细胞的罕见情况，人们必须真正认识到吞噬细胞所面临的工作的严重性。此外，由于这是生物体生命周期中反复发生的正常事件，这种泡腾过程必须以免疫沉默的方式发生，以免不适当地警告免疫系统。因此，吞噬细胞的反应必须根据货物和首选结果而量身定制。有效清除细胞外成分(无论是病原体或垂死的细胞)需要吞噬细胞首先识别并利用表面受体吞噬它们，然后处理货物并协调适当的局部和系统免疫反应。 然而，清除死亡细胞被设计为一种可容忍的机制，因为细胞死亡是一个正常的、基因编程的过程，旨在塑造、控制和帮助身体发育和生存。紧密协调的吞噬过程大致可分为4个步骤：1)死亡细胞产生的Find-Me信号招募吞噬细胞，2)吞噬细胞受体或桥分子识别和参与Eat-Me信号，3)吞噬细胞吞噬细胞身体，4)对吞噬身体的加工、降解和免疫反应。虽然已经完成了许多工作来表征负责吸引吞噬细胞并促进物理吞噬的分子，但吞噬细胞处理吞噬的身体的机制及其对后续免疫反应的影响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，对于清除病原体和濒临死亡的细胞以及指导随后对每个被吞噬的货物的免疫反应都是至关重要的。LC3相关的吞噬作用(LAP)是最近发现的一种途径，在吞噬过程中感受到特定的信号事件，并招募部分(但不是全部)自噬机制的成员到吞噬小体。正是这些自噬分子的活动，通过与溶酶体途径融合，促进了货物的快速破坏或处理。多种类型的受体，包括TLR1/2、TLR2/6、TLR4、FCR和TIM4的结合已被证明触发LAP形成单膜的、含有货物的吞噬小体，称为LAPosome。LAP是一个过程，它结合了进化上保守的吞噬和自噬途径，并允许我们重新想象自噬机制对固有宿主防御机制的影响。这种范式转换的实现将自噬机制的含义从细胞内内务扩展到宿主防御细胞外的威胁，并为炎症和自身免疫提供了新的线索。

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.