IL-33 induces immunosuppressive neutrophils via a type 2 innate lymphoid cell/IL-13/STAT6 axis and protects the liver against injury in LCMV infection-induced viral hepatitis
IL-33 induces immunosuppressive neutrophils via a type 2 innate lymphoid cell/IL-13/STAT6 axis and protects the liver against injury in LCMV infection-induced viral hepatitis
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DOI：
10.1038/cmi.2017.147
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发表时间：
2019-02-01
影响因子：
24.1
通讯作者：
Sun, Jiaren
中科院分区：
文献类型：
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作者：
Liang, Yuejin;Yi, Panpan;Sun, Jiaren
病毒性肝炎仍然是一个影响全球数百万人的公共卫生问题。中性粒细胞是多形核细胞，在抗菌感染中具有关键作用。然而，中性粒细胞在病毒感染中的作用尚未完全明确。通过使用淋巴细胞性脉络丛脑膜炎病毒感染诱导的病毒性肝炎小鼠模型，我们观察到肝脏中中性粒细胞募集增加，同时伴有CD8(+) T细胞应答增强。肝脏中性粒细胞高水平表达免疫调节细胞因子，如C - X - C趋化因子配体2、精氨酸酶 - 1、诱导型一氧化氮合酶和白细胞介素（IL）- 10，显示出免疫抑制特性。用中和抗体在体内耗竭中性粒细胞导致肝损伤加重，并在免疫收缩阶段促进T细胞应答。IL - 33显著诱导肝脏中中性粒细胞募集，并通过限制效应T细胞积累减轻肝损伤。从机制上讲，我们发现IL - 33通过2型固有淋巴细胞（ILC2）衍生的IL - 13促进中性粒细胞中精氨酸酶 - 1的表达。此外，IL - 13增加了中性粒细胞在体外对CD8(+) T细胞增殖的抑制作用，部分是通过精氨酸酶 - 1。最后，我们发现IL - 13诱导精氨酸酶 - 1表达依赖于信号转导和转录激活因子6（STAT6）信号通路。因此，IL - 33通过ILC2/IL - 13/STAT6轴诱导免疫抑制性中性粒细胞。总之，我们的研究结果为与肝脏中IL - 33触发的中性粒细胞相关的机制提供了新的见解，并为病毒性肝炎的治疗研究提出了潜在靶点。
Viral hepatitis is still a public health problem affecting several million people around the world. Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection. However, the role of neutrophils in viral infection is not fully understood. By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis, we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8(+) T-cell responses. Liver neutrophils expressed high levels of immunomodulatory cytokines, such as C-X-C chemokine ligand 2, arginase-1, inducible nitric oxide synthase and interleukin (IL)-10, demonstrating immunosuppressive properties. Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage. IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation. Mechanistically, we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell (ILC2)-derived IL-13. Additionally, IL-13 increased the inhibitory effect of neutrophils on CD8(+) T-cell proliferation in vitro, partially through arginase-1. Finally, we found that IL-13 induced arginase-1 expression, depending on signal transducer and activator of transcription factor 6 (STAT6) signaling. Therefore, IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis. Collectively, our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.