From acute pancreatitis to recurrent acute and chronic pancreatitis: Dynamic evolution of immune responses

Pancreatitis progresses from acute pancreatitis (AP) to chronic pancreatitis (CP) phases through dynamic immune cell transitions that determine disease resolution or fibrosis. In AP, rapid infiltration of neutrophils and M1-like macrophages drives tissue injury via cytokine storms, neutrophil extracellular traps (NETs), and inflammasome activation, while Th17 cells amplify inflammatory cascades. Resolution depends on phenotypic switching: M1-like macrophages transition to reparative M2-like states, regulatory T cells (Tregs) expand to suppress excessive inflammation, and dendritic cells shift from pro-inflammatory to regulatory functions. However, persistent injury disrupts this balance. In CP, macrophages become trapped in 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, whereas Tregs undergo functional failure and lose suppressive capacity. Concurrently, neutrophil activity becomes scattered and residual. Metabolic reprogramming fundamentally underpins these immune transitions. In AP, ketogenesis restrains macrophage hyperactivation and NLRP3 inflammasome signaling, while impaired fatty acid oxidation (FAO) and mitochondrial dysfunction in CP lock macrophages into glycolytic, pro-fibrotic phenotypes. Similarly, Th17 cells adopt glycolytic metabolism to sustain IL-17 production, whereas Treg suppressive function depends on intact oxidative phosphorylation, which is compromised in chronic disease. Iron overload and dysregulated neddylation further amplify oxidative stress and fibrotic signaling. These immune and metabolic alterations converge on PSC activation, establishing self-sustaining fibrotic loops. This review delineates the spatiotemporal dynamics of innate and adaptive immune cells across disease phases, emphasizing therapeutic opportunities targeting macrophage polarization, Th17/Treg balance, PSC-immune crosstalk, and metabolic checkpoints to interrupt AP-to-CP progression.