NONO regulates multiple cytokine production in sepsis via the ERK1/2 signaling pathway

Sepsis is a systemic inflammatory response syndrome caused by infection, leading to life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al., 2016). Essentially, sepsis is the body’s response to an infectious agent. More than a hundred years ago, Willian Osler observed that sepsis patients appeared to die in response to the infection, not the infection itself (Salomão et al., 2019). Although treatment strategies and methods are constantly updated, sepsis is still the leading cause of death from infection worldwide (Gyawali et al., 2019). One of the main causes of death from sepsis is the cytokine storm caused by excessive activation of the human immune system. Cytokine storm, also known as inflammatory storm, refers to the rapid and excessive production of many cytokines, such as tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), IL-6, IL-8, IL-12, interferon-α, interferon-γ, and monocyte chemoattractant protein-1 (MCP-1) in response to infection with microorganisms. The massive release of proinflammatory cytokines is a crucial step in triggering the inflammatory cascade effect in sepsis and a major cause of organ dysfunction and death (Lim, 2018). Inhibiting the production and release of proinflammatory cytokines is an important strategy for the treatment of sepsis, but clinical studies have found that the clinical effect of inhibiting one or two kinds of proinflammatory cytokines alone is not sufficient. Therefore, exploring the key molecules regulating the expression and release of many inflammatory cytokines has important value for revealing the mechanism of sepsis cytokine storm and subsequent sepsis treatment.

Human non-POU-domain-containing octamer binding protein (NONO), also known as 54 kDa nuclear RNA and DNA-binding protein, belongs to the Drosophila behavior human splicing family. Mouse Nono is orthologous to human NONO. NONO is a multifunctional nuclear protein in eukaryotic cells. There is growing evidence that NONO is involved in nearly every step of gene regulation, including mRNA splicing (Lu and Sewer, 2015), DNA unwinding (Fan et al., 2021), transcriptional regulation (Liang et al., 2020), nuclear retention of defective RNAs, and DNA damage repair (Vickers et al., 2019). We had previously reported that NONO knockdown inhibited TNF-α release from human leukemic monocyte THP1 cells stimulated by LPS (X. Zhang et al., 2016). However, the role of NONO in sepsis remains elusive. This study investigated the role of NONO and its potential mechanism in sepsis. This work is of great significance in revealing the mechanism of cytokine storm in sepsis and subsequent sepsis treatment.

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