Early Growth Response 1 Suppresses Macrophage Phagocytosis by Inhibiting NRF2 Activation Through Upregulation of Autophagy During Pseudomonas aeruginosa Infection.
Early Growth Response 1 Suppresses Macrophage Phagocytosis by Inhibiting NRF2 Activation Through Upregulation of Autophagy During Pseudomonas aeruginosa Infection.
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DOI：
10.3389/fcimb.2021.773665
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发表时间：
2021
影响因子：
5.7
通讯作者：
Zhu Q
中科院分区：
文献类型：
--
作者：
Pang Z;Xu Y;Zhu Q
铜绿假单胞菌是一种机会性病原体，在囊性纤维化患者和免疫功能低下的人中会导致危及生命的感染。健康人具有严密的免疫应答可以有效地控制铜绿假单胞菌的感染，而免疫应答异常的患者对这种细菌病原体易感。早期生长反应1(Egr-1)是一种锌指转录因子，参与包括免疫反应在内的多种细胞功能的调节。我们先前在急性铜绿假单胞菌肺炎小鼠模型中发现，Egr-1通过促进全身炎症和损害肺部细菌清除而对宿主有害，这与包括巨噬细胞和中性粒细胞在内的白细胞的吞噬和杀菌能力降低有关。然而，Egr-1抑制铜绿假单胞菌吞噬功能的分子机制还不完全清楚。在此，我们研究了在铜绿假单胞菌感染过程中，Egr-1调节的自噬是否通过Egr-1的过表达或下调在巨噬细胞吞噬中发挥作用。我们发现Egr-1过表达抑制了巨噬细胞的吞噬活性，自噬激活剂雷帕霉素和抑制剂氯喹分别逆转了Egr-1基因敲除和Egr-1过表达对铜绿假单胞菌吞噬功能的影响。此外，Egr-1过表达的巨噬细胞表现出自噬相关蛋白LC3A、LC3B和ATG5的表达上调，而p62的表达水平降低。进一步的研究表明，Egr-1基因敲除的巨噬细胞表现出转录因子NRF2的激活和清道夫受体MACRO和MSR1的表达增强。总之，这些发现表明Egr-1通过上调自噬和抑制NRF2信号通路来抑制巨噬细胞对铜绿假单胞菌的吞噬。
Pseudomonas aeruginosa is an opportunistic pathogen that causes life-threatening infections in cystic fibrosis patients and immunocompromised individuals. A tightly regulated immune response possessed by healthy individuals can effectively control P. aeruginosa infections, whereas the patients with dysregulated immune response are susceptible to this bacterial pathogen. Early growth response 1 (Egr-1) is a zinc-finger transcription factor involved in regulation of various cellular functions, including immune responses. We previously identified that Egr-1 was deleterious to host in a mouse model of acute P. aeruginosa pneumonia by promoting systemic inflammation and impairing bacterial clearance in lung, which associated with reduced phagocytosis and bactericidal ability of leucocytes, including macrophages and neutrophils. However, the molecular mechanisms underlying the Egr-1-suppressed phagocytosis of P. aeruginosa are incompletely understood. Herein, we investigated whether the Egr-1-regulated autophagy play a role in macrophage phagocytosis during P. aeruginosa infection by overexpression or knockdown of Egr-1. We found that overexpression of Egr-1 inhibited the phagocytic activity of macrophages, and the autophagy activator rapamycin and inhibitor chloroquine could reverse the effects of Egr-1 knockdown and Egr-1 overexpression on phagocytosis of P. aeruginosa, respectively. Furthermore, the Egr-1-overexpressing macrophages displayed upregulated expression of autophagy-related proteins LC3A, LC3B and Atg5, and decreased levels of p62 in macrophages. Further studies revealed that the macrophages with Egr-1 knockdown displayed enhanced activation of transcription factor NRF2 and expression of scavenger receptors MACRO and MSR1. Altogether, these findings suggest that Egr-1 suppresses the phagocytosis of P. aeruginosa by macrophages through upregulation of autophagy and inhibition of NRF2 signaling.
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DOI：
10.1084/jem.188.12.2215
发表时间：
1998-12-21
期刊：
The Journal of experimental medicine
影响因子：
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Britigan, Bradley E.
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影响因子：
5.7
作者：
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影响因子：
7.4
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16
作者：
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