NONO regulates multiple cytokine production in sepsis via the ERK1/2 signaling pathway. (January 2023)

• Record Type: Journal Article
• Authors: Niu, Ya; Xu, Guangyu; Zhu, Shaoping; Wei, Xiurong; Wu, Changli; Zhang, Ruigang; Chen, Chunling; Yan, Lvbin; Luo, Haihua; Deng, Simin; Wu, Weijian; Li, Yaojing; Liu, Ming; Jiang, Yong; Zhang, Xiujuan
• Is Part Of: Molecular immunology. Volume 153(2023)
• Page Start: 94
• Page End: 105
• Publication Date: 2023-01
• Subjects: NONO non-POU domain-containing octamer-binding protein -- ERK1/2 extracellular regulatory protein kinase 1/2 -- LPS lipopolysaccharide -- TNF-α tumor necrosis factor-α -- IL-1β interleukin 1beta -- IL-6 interleukin 6 -- MCP-1 monocyte chemoattractant protein-1 -- MIP-1α macrophage inflammatory protein-1 alpha -- MIP-1β macrophage inflammatory protein-1 beta -- GM-CSF granulocyte-monocyte colony-stimulating factor -- FCS fetal calf serum -- THP1-NONOi NONO-silencing THP1 cell -- THP1-NC negative control THP1 cell -- p-ERK phospho-ERK1/2 -- GAPDH glyceraldehyde-3-phosphate dehydrogenase -- i.p. intraperitoneal injection -- qPCR quantitative real-time PCR -- PVDF polyvinylidene fluoride -- PMA phorbol 12-myristate 13-acetate -- SD standard deviation -- MAPK mitogen-activated protein kinase -- Nono-KO Nono knockout mice; Non-POU domain containing octamer-binding protein -- Cytokine storm -- Sepsis -- Extracellular regulatory protein kinase 1/2; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2022.11.017
• Languages: English
• ISSNs: 0161-5890

Abstract

Abstract: 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, including IL-6, IL-1β, MCP-1, MIP-1α, and MIP-1β in 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. Nono knockout 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 of NONO knockdown. 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. NONO knockdown 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. Highlights: NONO expression was upregulated in sepsis mice. Nono knockout inhibited the expression and release of proinflammatory cytokines, and reduced the mortality of sepsis mice. NONO knockdown inhibited the expression and release of proinflammatory cytokines in lipopolysaccharide-induced THP1 cells. Reduced NONO expression inhibited the phosphorylation of ERK1/2 in mice and THP1 cells challenged by lipopolysaccharide. NONO and phospho-ERK1/2 colocalized in macrophages challenged by lipopolysaccharide.