Immunometabolic reprogramming of macrophages and neutrophils in acute pancreatitis: from metabolic stress to amplification and endogenous braking

Abstract

Acute pancreatitis (AP) progression involves both the initiating acinar injury and immune responses that sustain or contain subsequent damage. This review integrates evidence on metabolic regulation in macrophages and neutrophils to examine its links to inflammatory effectors, clearance, and tissue protection. Glycolytic regulation can support inflammatory activation, while non-AP neutrophil studies show how substrate allocation supports oxidant production and neutrophil extracellular trap (NET) release. Metabolite signaling also participates in macrophage efferocytosis, repair-associated responses, and tissue antioxidant defense. Contrasting lactate effects in acinar injury and macrophage repair indicate that metabolic changes must be interpreted through their effects on particular cells and functions. We propose an integrated amplification-braking framework that connects metabolically supported inflammatory effectors to continued generation of injury-derived stimuli, and clearance, antioxidant, and repair functions to damage containment. These functions can coexist without receiving equivalent metabolic support, and protective braking is distinct from generalized immunosuppression. Evidence differs across cells and experimental systems; metabolic regulation of inflammatory activation does not by itself establish metabolic control of NET-mediated injury in AP. The framework provides a basis for evaluating whether metabolic interventions can limit damaging activity while preserving protective functions, but it is not a validated clinical model. Pairing metabolic changes with specific cellular functions and subsequent injury is central to testing these relationships.