背景:视网膜变性是由于损伤引起的视网膜稳态破坏,疾病,或老化并引发外周白细胞浸润。有效的免疫反应依赖于常驻小胶质细胞和招募的巨噬细胞的协调行动,对于组织重塑和修复至关重要。然而,这些吞噬细胞也有助于变性视网膜的慢性炎症,然而,对视网膜损伤的免疫反应的精确协调仍然难以捉摸。最近的研究表明,吞噬细胞可以产生细胞外陷阱(ETs),它们是改变免疫反应的自身抗原的来源,这可能会导致组织损伤。
方法:实验系统的创新促进了免疫细胞相互作用和动态反应的实时探索。我们整合了体内成像和超微结构分析,转录组学,药物治疗,和敲除小鼠,以阐明吞噬细胞的作用及其通过细胞外陷阱(ET)调节局部炎症反应。解密这些机制对于开发新的和增强的免疫治疗方法是必不可少的,该方法可以将特定的适应性不良免疫应答重定向到视网膜中有利的伤口愈合。
结果:我们的发现强调了先天免疫细胞的关键作用,尤其是巨噬细胞/单核细胞,调节视网膜修复和炎症。中性粒细胞和巨噬细胞浸润的缺乏有助于实质完整性恢复,当它们耗尽时,特别是巨噬细胞/单核细胞,阻碍血管恢复。我们证明巨噬细胞/单核细胞,当在视网膜中招募时,释放染色质和颗粒蛋白,形成ET。此外,ETosis的药理学抑制支持视网膜和血管修复,超越阻断先天免疫细胞募集的影响。同时,ETosis的缺失重塑了炎症反应,导致嗜中性粒细胞,助手,和细胞毒性T细胞主要限制在浅表毛细血管丛中,而不是到达受损的感光层。
结论:我们的数据提供了有关先天免疫在应对视网膜损伤中的作用的新见解,并可能有助于开发创新的免疫治疗方法,将免疫反应从适应不良转变为有益于视网膜再生。
BACKGROUND: Retinal degeneration results from disruptions in retinal homeostasis due to injury, disease, or aging and triggers peripheral leukocyte infiltration. Effective immune responses rely on coordinated actions of resident microglia and recruited macrophages, critical for tissue remodeling and repair. However, these phagocytes also contribute to chronic inflammation in degenerated retinas, yet the precise coordination of immune response to retinal damage remains elusive. Recent investigations have demonstrated that phagocytic cells can produce extracellular traps (ETs), which are a source of self-antigens that alter the immune response, which can potentially lead to tissue injury.
METHODS: Innovations in experimental systems facilitate real-time exploration of immune cell interactions and dynamic responses. We integrated in vivo imaging with ultrastructural analysis, transcriptomics, pharmacological treatments, and knockout mice to elucidate the role of phagocytes and their modulation of the local inflammatory response through extracellular traps (ETs). Deciphering these mechanisms is essential for developing novel and enhanced immunotherapeutic approaches that can redirect a specific maladaptive immune response towards favorable wound healing in the retina.
RESULTS: Our findings underscore the pivotal role of innate immune cells, especially macrophages/monocytes, in regulating retinal repair and inflammation. The absence of neutrophil and macrophage infiltration aids parenchymal integrity restoration, while their depletion, particularly macrophages/monocytes, impedes vascular recovery. We demonstrate that macrophages/monocytes, when recruited in the retina, release chromatin and granular proteins, forming ETs. Furthermore, the pharmacological inhibition of ETosis support retinal and vascular repair, surpassing the effects of blocking innate immune cell recruitment. Simultaneously, the absence of ETosis reshapes the inflammatory response, causing neutrophils, helper, and cytotoxic T-cells to be restricted primarily in the superficial capillary plexus instead of reaching the damaged photoreceptor layer.
CONCLUSIONS: Our data offer novel insights into innate immunity\'s role in responding to retinal damage and potentially help developing innovative immunotherapeutic approaches that can shift the immune response from maladaptive to beneficial for retinal regeneration.