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 remains unclear. Here we explored the mechanisms through which NEAT1 may regulate neutrophil activities in the context of UC. We collected colon biopsies from UC patients for the purpose of NEAT1 detection. A model of colitis induced by dextran sulfate sodium (DSS) was created using NEAT1 gene knockout (NEAT1 KO) mice, to investigate the contribution of NEAT1 to intestinal inflammation. The impact of NEAT1 on neutrophil activities was assessed through single-cell RNA sequencing, flow cytometry, immunofluorescence, RNA sequencing, and the Seahorse metabolic assay. We found that NEAT1 expression was elevated in the inflamed mucosa of UC patients, showing a positive correlation with the disease activity. NEAT1 KO mice exhibited less severe intestinal mucosal inflammation after 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, indicating that NEAT1 could serve as a promising target for treatment of UC.
Zhu et al. (Thu,) studied this question.