Immune and metabolic shifts drive acute pancreatitis into chronic disease

Pancreatitis is clinically classified into acute pancreatitis (AP) and chronic pancreatitis (CP). Most patients with AP recover without residual pancreatic dysfunction; a subset develops recurrent AP, and only selected high-risk individuals-particularly those with ongoing etiological exposure, genetic susceptibility, or severe necrotizing disease-progress to CP. The mechanisms underlying this progression remain poorly understood.

In AP, rapid infiltration of neutrophils and M1-like macrophages drives tissue injury through cytokine release, neutrophil extracellular traps, and inflammasome activation, while T helper 17 (Th17) cells amplify inflammation. Resolution depends on phenotypic switching: M1-like macrophages shift to reparative M2-like states, regulatory T cells (Tregs) expand, and dendritic cells shift from pro-inflammatory to regulatory functions. Persistent injury disrupts this balance. In CP, macrophages become trapped in an incomplete M2-like polarization, retaining pro-inflammatory features while acquiring pro-fibrotic functions; pathogenic Th17 cells persist and directly activate pancreatic stellate cells (PSCs) via IL-17A and IL-22; Tregs undergo functional failure; and neutrophil activity becomes scattered and residual.

Metabolic reprogramming underpins these transitions. In AP, ketogenesis restrains macrophage hyperactivation and NLRP3 signaling, whereas impaired fatty acid oxidation and mitochondrial dysfunction in CP lock macrophages into glycolytic, pro-fibrotic phenotypes. Th17 cells adopt glycolysis to sustain IL-17 production, while Treg suppression depends on oxidative phosphorylation that is compromised in chronic disease. Iron overload and dysregulated neddylation further amplify oxidative stress and fibrotic signaling. These changes converge on PSC activation, establishing self-sustaining fibrotic loops.

The review, published in Volume 9, Issue 3 of the Journal of Pancreatology in September 2026, delineates spatiotemporal dynamics of innate and adaptive immune cells across disease phases and identifies therapeutic opportunities targeting macrophage polarization, Th17/Treg balance, PSC–immune crosstalk, and metabolic checkpoints. It was based on a PubMed search supplemented by Embase and Web of Science, restricted to English articles published from January 2016 to July 2026, with the exception of seminal studies identified through cross-referencing.