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SOCS3-deficient lung epithelial cells uptaking neutrophil-derived SOCS3 worsens lung influenza infection.
Molecular Immunology ( IF 3.6 ) Pub Date : 2020-07-06 , DOI: 10.1016/j.molimm.2020.06.022
Ling Li 1 , Haiya Wu 1 , Qingmei Li 1 , Jie Chen 1 , Kaifeng Xu 2 , Jinfu Xu 3 , Xiao Su 1
Affiliation  

Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of TBK1 and interferon pathway and the expression of SOCS3 is closely correlated with symptoms of influenza patients. However, whether deletion of Socs3 in the lung epithelial cells would affect influenza lung replication and inflammation in vivo is unknown. To test this, we approached the influenza infected Socs3f/f and SpcCre.Socs3f/f mice. We first found that knockdown of Socs3 in lung epithelial cells reduced influenza replication. However, in the in vivo study, there was a reduction of SOCS3 in the influenza-infected neutrophils coincided with an increase of SOCS3 in the CD45CD326+ lung epithelial cells in PR8-infected SpcCre.Socs3f/f mice. SOCS3-deficient neutrophils expressed higher levels of IL-17 that enhanced chemokine expression in the lung epithelial cells. Lung SOCS3-dificient epithelial cells increased expression of GM-CSF and PGE2 which promoted SpcCre.Socs3f/f neutrophils to yield SOCS3. SpcCre.Socs3f/f lung epithelial cells internalized SOCS3 released from GM-CSF + PGE2-stimulated SpcCre.Socs3f/f neutrophils, which could boost influenza replication in the lung epithelial cells. Thus, in the in vivo study, deletion of SOCS3 from lung epithelium could be nullified by the uptake from SOCS3 from infiltrated neutrophils. In addition, deletion of Socs3 from myeloid cells reduced lung influenza infection, but increased lung inflammation. Taken together, deletion of SOCS3 could suppress influenza replication, but intracellular SOCS3 communication between neutrophils and lung epithelial cells confounds this effect.



中文翻译:

摄取中性粒细胞来源的SOCS3的SOCS3缺陷型肺上皮细胞会使肺部流感感染恶化。

细胞因子信号传导抑制因子3(SOCS3)是TBK1和干扰素途径的负调控因子,SOCS3的表达与流感患者的症状密切相关。但是,尚不清楚肺上皮细胞中Socs3的缺失是否会影响流感的肺复制和体内炎症。为了测试这一点,我们接触了感染了流感的Socs3 f / fSpcCre.Socs3 f / f小鼠。我们首先发现敲肺上皮细胞中的Socs3会减少流感的复制。但是,在体内研究中,流感感染的中性粒细胞中的SOCS3减少,而CD45中的SOCS3增加。 PR8感染的SpcCre.Socs3 f / f小鼠中的CD326 +肺上皮细胞。缺乏SOCS3的中性粒细胞表达更高水平的IL-17,从而增强了肺上皮细胞中趋化因子的表达。缺乏SOCS3的肺上皮细胞增加GM-CSF和PGE 2的表达,从而促进SpcCre.Socs3 f / f中性粒细胞产生SOCS3。SpcCre.Socs3 f / f肺上皮细胞内化了从GM-CSF + PGE 2刺激的SpcCre.Socs3 f / f中性粒细胞释放的SOCS3 ,这可能会促进流感在肺上皮细胞中的复制。因此,在体内在一项研究中,肺上皮中SOCS3的缺失可以被浸润的中性粒细胞中SOCS3的吸收抵消。此外,从髓样细胞中删除Socs3可以减少肺部流感的感染,但会增加肺部炎症。两者合计,删除SOCS3可以抑制流感的复制,但嗜中性粒细胞和肺上皮细胞之间的细胞内SOCS3通讯会混淆这种效果。

更新日期:2020-07-06
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