Key points are not available for this paper at this time.
Acute pancreatitis (AP) is an inflammatory disorder that escalate rapidly from localized pancreatic injury to systemic inflammation and multi-organ failure. Dysregulated innate immunity is central to AP pathogenesis: acinar cell injury releases damage-associated molecular patterns (DAMPs), triggering an inflammatory cascade. However, the molecular mediators that amplify and sustain systemic immune activation remain elusive. Here, through integrated bulk and single-cell transcriptomes analyses of human AP patients and murine models, we identified N-myc and STAT interactor (NMI) as a DAMP mediator consistently upregulated in the pancreas, circulation, and distant organs during AP. NMI expression was enriched in macrophages and neutrophils, and circulating NMI distinguished AP patients from healthy controls with high diagnostic accuracy. Mechanistically, recombinant NMI directly activated macrophages, inducing rapid PI3K-AKT phosphorylation and secretion of pro-inflammatory cytokines IL-6 and TNF, while single-cell communication analysis revealed IL-6 as a dominant downstream effector. In vivo, both genetic ablation of Nmi and pharmacologic inhibition of PI3K-AKT signaling attenuated pancreatic injury, mitigated lung involvement, and reduced systemic cytokine release in severe AP(SAP). Collectively, these findings establish NMI as a mechanistic driver and biomarker of AP, with translational potential as a therapeutic target to curb excessive inflammation and improve outcomes.
Guo et al. (Mon,) studied this question.