Gpr174-deficient regulatory T cells decrease cytokine storm in septic mice.,Cell Death & Disease

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Gpr174-deficient regulatory T cells decrease cytokine storm in septic mice.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-03-08 , DOI: 10.1038/s41419-019-1462-z
Dongze Qiu _{1,

2} , Xun Chu _{3,

4} , Laiqing Hua ₅ , Yunke Yang ₂ , Keyong Li ₆ , Yi Han ₁ , Jun Yin ₁ , Ming Zhu ₁ , Sucheng Mu ₁ , Zhan Sun ₁ , Chaoyang Tong ₁ , Zhenju Song ₁

Affiliation

G protein-coupled receptor 174 (GPR174) is mainly expressed in thymus, spleen, lymph nodes, and leukocytes, and genetic variation in GPR174 is associated with susceptibility to autoimmune diseases, indicating that GPR174 is involved in the immune response. However, the function of GPR174 in regulating inflammatory responses against bacterial infection in sepsis remains unclear. In this study, we investigated the role of GPR174 in regulating suppressive function of regulatory T cells (Treg cells) and the underlying mechanism of Gpr174-deficient Treg cells in controlling cytokine storm of sepsis. We showed that Gpr174-dedicient mice were resistant to inflammatory shock induced by lipopolysaccharide (LPS) and cecal ligation and puncture (CLP). Moreover, Gpr174 was highly expressed in Treg cells, and its deficiency in mice promoted the expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and interleukin (IL)-10 in Treg cells. By using the LPS-induced sepsis model, we demonstrated that anti-inflammatory macrophages (M2 macrophages) induction was Treg cell-dependent and Gpr174-deficient Treg cells protected mice against sepsis-induced lung damage through prompting M2 macrophages polarization. In vitro, Gpr174-deficient Treg cells also promoted the polarization of macrophages toward M2 cells and dampened the secretions of pro-inflammatory cytokines (IL-6 and tumor necrosis factor-α (TNF-α)) in macrophages. In conclusion, these findings suggested that GPR174 plays an important role in the initial period of sepsis through the regulation of macrophage polarization and pro- and anti-inflammatory cytokine secretions. Therefore, GPR174 may be a promising target for therapeutic agents to regulate inflammatory disorders.

中文翻译：

缺乏Gpr174的调节性T细胞减少败血症小鼠的细胞因子风暴。

G蛋白偶联受体174（GPR174）主要在胸腺，脾脏，淋巴结和白细胞中表达，GPR174的遗传变异与自身免疫性疾病的易感性有关，表明GPR174参与了免疫反应。然而，GPR174在调节败血症中针对细菌感染的炎症反应中的功能仍不清楚。在这项研究中，我们调查了GPR174在调节调节性T细胞（Treg细胞）的抑制功能中的作用以及Gpr174缺陷型Treg细胞在控制败血症细胞因子风暴中的潜在机制。我们显示，Gpr174依赖的小鼠对脂多糖（LPS）和盲肠结扎穿刺（CLP）诱导的炎症休克具有抵抗力。此外，Gpr174在Treg细胞中高表达，小鼠中的这种缺陷及其促进了Treg细胞中细胞毒性T淋巴细胞相关抗原4（CTLA-4）和白介素（IL）-10的表达。通过使用LPS诱导的脓毒症模型，我们证明了抗炎巨噬细胞（M2巨噬细胞）诱导是Treg细胞依赖性的，而Gpr174缺陷型Treg细胞则通过促使M2巨噬细胞极化来保护小鼠免受脓毒症诱导的肺损伤。在体外，缺乏Gpr174的Treg细胞还促进巨噬细胞向M2细胞极化，并抑制巨噬细胞中促炎性细胞因子（IL-6和肿瘤坏死因子-α（TNF-α））的分泌。总之，这些发现表明，GPR174在脓毒症的初始阶段通过调节巨噬细胞极化以及促炎和抗炎性细胞因子的分泌发挥重要作用。所以，

更新日期：2019-03-09

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