NEAT1 modulates neutrophil functions via glycolysis to restrain mucosal inflammation in ulcerative colitis

Neutrophils are essential for maintaining intestinal mucosal balance during ulcerative colitis (UC). The long noncoding RNA known as nuclear paraspeckle assembly transcript 1 (NEAT1) is associated with various inflammatory disorders. Nonetheless, the role of NEAT1 in influencing neutrophil immune responses in the context of UC remains unclear. In this study, we observed that NEAT1 expression was elevated in the inflamed mucosa of UC patients, showing a positive correlation with the disease activity. NEAT1 gene knockout (NEAT1 KO) mice exhibited less severe intestinal mucosal inflammation after dextran sulfate sodium (DSS) treatment. NEAT1 was predominantly expressed in neutrophils and elevated in neutrophils from UC patients. A deficiency in NEAT1 resulted in immune function remodeling of neutrophils, including a reduction in the production of pro-inflammatory cytokines, chemokines, reactive oxygen species, and neutrophil extracellular traps both in vitro and in vivo. Mechanistically, NEAT1 regulated neutrophil functions partially via glycolysis. Our research reveals a new mechanism through which NEAT1 influences the pathological development of UC by limiting the overactivation of neutrophils via glycolysis, providing a rationale for targeting NEAT1 in UC treatment.