Aged Neutrophils Drive IBD Inflammation and May Be a New Drug Target

Inflammatory bowel disease (IBD) remains difficult to treat partly because the exact immune mechanisms driving chronic intestinal inflammation are incompletely understood. Neutrophils, often viewed primarily as first-line defenders, can also perpetuate tissue damage—and a specific subset called 'aged' neutrophils (marked by CXCR4 high expression and low CD62L) may be particularly culpable.

This study from Southern Medical University enrolled 61 IBD patients—47 with active disease and 14 in remission—alongside 36 healthy controls. Peripheral blood and colonic biopsies were analyzed to quantify aged neutrophils. Flow cytometry, immunofluorescence, and co-culture experiments were used to characterize their functional behavior.

Key results showed a marked accumulation of aged neutrophils in both the blood and inflamed intestinal tissue of active IBD patients, with counts correlating positively with disease severity scores. Functionally, these cells exhibited elevated β-galactosidase activity (a cellular senescence marker), heightened reactive oxygen species production, enhanced neutrophil extracellular trap (NET) formation, and increased secretion of IL-6, IL-17A, and TNF-α. Crucially, they also promoted T- and B-cell activation, suggesting they act as a bridge between innate and adaptive immunity.

In a dextran sulfate sodium mouse model of acute colitis, treatment with the CXCR4 antagonist AMD3100 reduced aged neutrophil accumulation, lowered inflammatory markers, and restored gut barrier integrity by upregulating tight junction proteins ZO-1 and occludin.

The study positions aged neutrophils as amplifiers of IBD pathology rather than simple bystanders. However, findings are based partly on correlative clinical data and a single acute animal model, so causal human evidence and long-term safety of CXCR4 blockade remain to be established.