Neutrophils drive pancreatic inflammation and tissue injury but promote tissue repair in severe acute pancreatitis.

Severe acute pancreatitis (SAP) has no targeted therapeutic options, largely owing to incomplete understanding of the mechanisms governing the transition from tissue injury to repair. Neutrophils are central effectors of sever acute pancreatitis, but their temporal contribution to injury and repair remains unresolved. Neutrophil depletion was therefore timed to defined disease stages using ROSA26iDTR/MRP8-Cre mice, in which diphtheria toxin administration was initiated on day 0, day 1, or day 2 after caerulein-induced pancreatitis; depletion efficiency was confirmed by flow cytometry. Depletion initiated on day 0 (early injury phase) reduced pancreatic injury on day 2, and histological recovery from day 4 to day 8 was more complete than in controls, a difference best explained by a reduced initial damage burden rather than a direct effect on the repair program. Depletion initiated on day 1 (late injury phase) altered neither injury nor recovery. In contrast, depletion initiated on day 2 (regenerative phase) impaired repair, with persistent acinar-to-ductal metaplasia, prolonged CD45+ infiltration, and expansion of CD86+ cells (pro-inflammatory macrophages). Neutrophils therefore function sequentially as mediators of early pancreatic injury and as required contributors to subsequent resolution, supporting that neutrophil-directed therapy should be timed to suppress pathogenic activity while preserving repair.