Lack of S1PR2 in Macrophage Ameliorates Sepsis-associated Lung Injury through Inducing IL-33-mediated Type 2 Immunity
Lack of S1PR2 in Macrophage Ameliorates Sepsis-associated Lung Injury through Inducing IL-33-mediated Type 2 Immunity
复制标题
巨噬细胞缺乏S1PR2可通过诱导il -33介导的2型免疫改善败血症相关肺损伤
DOI：
10.1165/rcmb.2023-0075oc
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发表时间：
2024-03-01
影响因子：
6.4
通讯作者：
Shu，Qiang
中科院分区：
文献类型：
--
作者：
Gong，Chenchen;Jin，Yue;Shu，Qiang
脓毒症所致肺损伤后2型免疫的功能和启动2型免疫的机制尚不清楚。鞘氨醇-1-磷酸受体2(S1PR2)已被证明在哮喘和肺纤维化的背景下调节2型免疫。因此，本研究旨在探讨2型免疫在脓毒症中的作用以及S1PR2是否以及如何调节2型免疫在脓毒症中的作用。对脓毒症患者和健康对照组的外周2型免疫反应进行了评估。进一步研究了S1PR2对脓毒症患者和脓毒症小鼠模型中2型免疫功能的影响。脓毒症后24 患者循环中的2型天然免疫反应显著升高，与临床并发症呈正相关，与S1PR2mRNA的表达呈负相关。动物实验表明，S1PR2基因缺失或药物抑制可诱导败血症后肺组织中的2型先天免疫蓄积。从机制上讲，S1PR2缺乏促进肺内巨噬细胞衍生的白介素33的增加和相关的2型反应。此外，S1PR2调节的巨噬细胞产生的IL-33减轻了脓毒症小鼠的肺损伤。总之，缺乏S1PR2通过上调巨噬细胞释放IL-33来调节2型免疫反应，并减轻脓毒症引起的肺损伤。靶向S1PR2可能对脓毒症的治疗具有潜在的治疗价值。
The function of type 2 immunity and mechanisms underlying the initiation of type 2 immunity after sepsis-induced lung injury remain unclear. Sphingosine-1-phosphate receptor 2 (S1PR2) has been demonstrated to modulate type 2 immunity in the context of asthma and pulmonary fibrosis. Thus, this study aims to investigate the role of type 2 immunity and whether and how S1PR2 regulates type 2 immunity in sepsis. Peripheral type 2 immune responses in patients with sepsis and healthy control subjects were assessed. The impact of S1PR2 on type 2 immunity in patients with sepsis and in a murine model of sepsis was further investigated. The type 2 innate immune responses were significantly increased in the circulation of patients 24 hours after sepsis, which was positively related to clinical complications and negatively correlated withS1PR2mRNA expression. Animal studies showed that genetic deletion or pharmacological inhibition of S1PR2 induced type 2 innate immunity accumulation in the post-septic lungs. Mechanistically, S1PR2 deficiency promoted macrophage-derived interleukin (IL)-33 increase and the associated type 2 response in the lung. Furthermore, S1PR2-regulated IL-33 from macrophages mitigated lung injury after sepsis in mice. In conclusion, a lack of S1PR2 modulates the type 2 immune response by upregulating IL-33 release from macrophages and alleviates sepsis-induced lung injury. Targeting S1PR2 may have potential therapeutic value for sepsis treatment.