Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, China; Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Immunity. 2021 Jun 8;54(6):1123-1136.e8. doi: 10.1016/j.immuni.2021.05.007.
Neutrophils migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis. Here we investigated the mechanisms whereby neutrophils participate in tissue repair. In an intestinal epithelia injury model, neutrophil depletion exacerbated colitis and associated with reduced interleukin (IL)-22 and limited activation of type 3 innate lymphoid cells (ILC3s). Co-culture with neutrophils activated ILC3s in a manner dependent on neutrophil apoptosis. Metabolomic analyses revealed that lysophosphatidylserine (LysoPS) from apoptotic neutrophils directly stimulated ILC3 activation. ILC3-specific deletion of Gpr34, encoding the LysoPS receptor GPR34, or inhibition of downstream PI3K-AKT or ERK suppressed IL-22 production in response to apoptotic neutrophils. Gpr34 mice exhibited compromised ILC3 activation and tissue repair during colon injury, and neutrophil depletion abrogated these defects. GPR34 deficiency in ILC3s limited IL-22 production and tissue repair in vivo in settings of colon and skin injury. Thus, GPR34 is an ILC3-expressed damage-sensing receptor that triggers tissue repair upon recognition of dying neutrophils.
中性粒细胞迅速迁移到受损组织，并在宿主防御和组织稳态中发挥关键作用。在这里，我们研究了中性粒细胞参与组织修复的机制。在肠上皮损伤模型中，中性粒细胞耗竭使结肠炎恶化，并与白细胞介素 (IL)-22 减少和 3 型固有淋巴细胞 (ILC3) 的有限激活相关。与中性粒细胞共培养以依赖中性粒细胞凋亡的方式激活 ILC3。代谢组学分析显示，来自凋亡中性粒细胞的溶血磷脂酰丝氨酸 (LysoPS) 直接刺激 ILC3 的激活。ILC3 特异性缺失 Gpr34（编码 LysoPS 受体 GPR34）或抑制下游 PI3K-AKT 或 ERK 可抑制对凋亡中性粒细胞的 IL-22 产生。Gpr34 小鼠在结肠损伤期间表现出 ILC3 激活和组织修复受损，而中性粒细胞耗竭则消除了这些缺陷。在结肠和皮肤损伤的情况下，ILC3 中的 GPR34 缺陷限制了 IL-22 的产生和组织修复。因此，GPR34 是一种 ILC3 表达的损伤感应受体，在识别死亡中性粒细胞时触发组织修复。
