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

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.

Keywords: Cytokine storm; Extracellular regulatory protein kinase 1/2; Non-POU domain containing octamer-binding protein; Sepsis.