NONO regulates multiple cytokine production in sepsis via the ERK1/2 signaling pathway.
NONO regulates multiple cytokine production in sepsis via the ERK1/2 signaling pathway.
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DOI：
10.1016/j.molimm.2022.11.017
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发表时间：
2022-11
影响因子：
3.6
通讯作者：
Y-Q Niu;Guangyu Xu;Shao-ping Zhu;Xiurong Wei;Changli Wu;Rui-Gang Zhang;Chun-Ling Chen;Lvbin Yan-L
中科院分区：
文献类型：
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作者：
Y-Q Niu;Guangyu Xu;Shao-ping Zhu;Xiurong Wei;Changli Wu;Rui-Gang Zhang;Chun-Ling Chen;Lvbin Yan-L
促炎细胞因子的大量释放是引发脓毒症炎症级联反应的关键步骤。探索多种细胞因子表达和释放的关键分子对揭示脓毒症中细胞因子风暴的机制具有重要价值。本研究旨在探讨含有八聚体结合蛋白（NONO）的多功能核蛋白非pou结构域在脓毒症细胞因子风暴中的作用，并阐明其潜在机制。我们发现NONO在脓毒症小鼠的组织和细胞中的表达明显上调。下调NONO表达可抑制脂多糖（LPS）刺激小鼠和人白血病单核细胞THP1炎症细胞中il -6、IL-1β、MCP-1、MIP-1α和mip -1β等多种细胞因子的mRNA表达，并显著降低LPS刺激的THP1细胞上清液中这些细胞因子和TNF-α的水平。非敲除还能降低血清中TNF-α、IL-6、MIP-1α和MIP-1β的水平，减轻肝细胞水肿，提高脓毒症小鼠的存活率。NONO表达的降低降低了脓毒症小鼠炎症细胞或LPS刺激的THP1细胞的磷酸化erk1 /2水平。Phospho-ERK1/2 inhibitor可降低lps诱导的THP1细胞培养上清中mRNA的表达和细胞因子的浓度，与nonoknockdown的作用相似。LPS刺激后，巨噬细胞内磷酸化- erk1 /2和NONO水平升高，并在细胞核和囊泡样细胞器内明显共定位。nonknockdown减少了磷酸化- erk1 /2在lps刺激的THP1细胞中的核易位。这些结果表明NONO是一个潜在的关键分子，参与脓毒症中多种细胞因子的产生。脓毒症中NONO的上调可能通过促进ERK1/2磷酸化，促进多种细胞因子的表达和释放，参与脓毒症细胞因子风暴。
The massive release of pro-inflammatory cytokines is a crucial step in triggering the inflammatory cascade in sepsis. Exploring the key molecules regulating the expression and release of multiple cytokines has important value for revealing the mechanism of the cytokine storm in sepsis. This study aimed to investigate the role of multifunctional nuclear protein non-POU domain containing octamer-binding protein (NONO) in the sepsis cytokine storm and to elucidate the underlying mechanism. We found that NONO expression in tissues and cells of sepsis mice was significantly upregulated. Downregulation of NONO expression inhibited the mRNA expression of multiple cytokines, includingIL-6, IL-1β, MCP-1, MIP-1α, and MIP-1βin inflammatory cells from mice and human leukemic monocyte-THP1 cells challenged with lipopolysaccharide (LPS), and significantly decreased the level of these cytokines and TNF-α in the supernatant of THP1 cells challenged by LPS.Nonoknockout also reduced the levels of TNF-α, IL-6, MIP-1α, and MIP-1β in serum, alleviated hepatocyte edema, and improved the survival rate of sepsis mice. Reduced NONO expression decreased the phospho-ERK1/2 level in inflammatory cells from sepsis mice or THP1 cells challenged by LPS. Phospho-ERK1/2 inhibitor decreased the mRNA expression and concentration of cytokines in the culture supernatant of LPS-induced THP1 cells, similar to the effect ofNONOknockdown. After LPS challenge, the levels of phospho-ERK1/2 and NONO were increased, with obvious colocalization in the nucleus and vesicular-like organelles in macrophages.NONOknockdown decreased nuclear translocation of phospho-ERK1/2 in LPS-challenged THP1 cells. These results suggest that NONO is a potentially critical molecule involved in multiple cytokine production in sepsis. Upregulated NONO in sepsis may promote the expression and release of multiple cytokines to participate in a sepsis cytokine storm by promoting ERK1/2 phosphorylation.