Resolution of neutrophil response for effective T cell functions and tissue repair

项目总结/摘要-项目1 中性粒细胞迁移到组织感染部位对于病原体清除和宿主存活至关重要。 重要的是，一旦它们完成了它们的作用，在感染早期阶段浸润的中性粒细胞应该 快速启动自发凋亡。中性粒细胞消退延迟通常与广泛的 组织损伤、器官衰竭，最终导致严重感染患者死亡。因此， 长期以来，人们一直认为感染期间未解决的中性粒细胞反应是有害的， 患者很难康复。虽然越来越多的证据表明，中性粒细胞不仅有助于 组织损伤，但也协调T细胞功能和组织修复，它一直具有挑战性，清楚地 将中性粒细胞的宿主保护作用与其破坏性炎症功能区分开来，因为大多数 这些研究使用了过度激活或不适当的炎症反应， 体内平衡因此，嗜中性粒细胞对宿主免疫应答和组织修复的贡献可能不 在这些模型中进行适当的评估。我们进行这项研究，以解决关键的知识差距， 感染期间中性粒细胞的功能和命运。通过我们初步调查中的几条线索 研究使用完全恢复的小鼠流感感染模型，我们提出了中性粒细胞的新功能， 可积极促进组织愈合和炎症消退。我们发现凋亡 嗜中性粒细胞积极参与其它周围细胞的增殖和存活（例如，上皮细胞 和巨噬细胞）。凋亡中性粒细胞的促有丝分裂和促存活作用主要是由 表皮生长因子（EGF）此外，我们的活体多光子显微镜（IV-MPM） 新产生的Ly 6 GCre/ROSAtdTomato/Csf 1 r-EGFP小鼠显示了显著的中性粒细胞运动模式， 它们的吞噬细胞在感染气道内的消退阶段，这可能代表了额外的 中性粒细胞在保护宿主免受感染方面的有益功能。我们假设， 流感感染期间的中性粒细胞反应不仅仅是早期中性粒细胞的被动终止， 而是一个积极的生物化学和细胞过程，以建立有效的T细胞免疫应答 同时使组织能够修复并恢复正常功能。我们将检验以下假设：（1）凋亡 嗜中性粒细胞促进组织修复和（2）嗜中性粒细胞控制它们自身的清除。我们还将确定（3） 中性粒细胞消退是否调节T细胞功能和记忆形成。因为重要的免疫系统- 中性粒细胞的调节特性，了解中性粒细胞在解决 可以利用炎症来对抗感染和慢性炎症。

PROJECT SUMMARY/ABSTRACT – PROJECT 1 Migration of neutrophils to sites of tissue infection is vital for pathogen clearance and, thus, host survival. Importantly, once they complete their action, infiltrated neutrophils during the early infection phase should quickly initiate spontaneous apoptosis. A delayed neutrophil resolution is often associated with widespread tissue damage, organ failure, and ultimately death in severely infected patients. Therefore, the presence of unresolved neutrophil response during infection has long been believed to be detrimental, making it more difficult for patients to recover. Although growing evidence now suggests that neutrophils not only contribute to the tissue damage, but also orchestrate T cell functions and tissue repair, it has been challenging to clearly differentiate host-protective roles of neutrophils from their damaging inflammatory functions because most of the studies used over-activated or inappropriate inflammatory responses, which fail to restore tissue homeostasis. Therefore, the contribution of neutrophils to the host immune response and tissue repair may not be properly evaluated in these models. We undertook this study to address critical knowledge gaps regarding the function and fate of neutrophils during the infection. Through several lines of evidence from our preliminary study using a fully recovering mouse influenza infection model, we propose novel functions of neutrophil that can actively promote tissue healing and the resolution of inflammation. We discovered that apoptotic neutrophils actively engage with the proliferation and survival of other surrounding cells (e.g., epithelial cells and macrophages). This mitogenic and pro-survival effect of apoptotic neutrophils was mainly mediated by the secretion of epidermal growth factor (EGF). Moreover, live intravital multiphoton microscopy (IV-MPM) of our newly generated Ly6GCre/ROSAtdTomato/Csf1r-EGFP mice revealed a striking motility pattern of neutrophils and their phagocytes during the resolution phase within the infected airway, which may represent additional beneficial functions of neutrophils in protecting the host against infections. We hypothesize that resolution of neutrophil response during influenza infection is not merely a passive termination of the early neutrophil infiltrates but rather an active biochemical and cellular process to establish effective T cell immune responses while enabling tissues to repair and return to normal function. We will test the hypothesis that (1) apoptotic neutrophils promote tissue repair and (2) neutrophils control their own clearance. We will also determine (3) whether neutrophil resolution regulates T cell functions and memory formation. Given the important immune- modulatory properties of neutrophils, understanding of novel functions of neutrophil during the resolution of inflammation could be harnessed to combat infection and chronic inflammatory conditions.