Damage associated molecular patterns and neutrophil extracellular traps in acute pancreatitis

Abstract

Previous researches have emphasized a trypsin-centered theory of acute pancreatitis (AP) for more than a century. With additional studies into the pathogenesis of AP, new mechanisms have been explored. Among them, the role of immune response bears great importance. Pro-inflammatory substances, especially damage-associated molecular patterns (DAMPs), play an essential role in activating, signaling, and steering inflammation. Meanwhile, activated neutrophils attach great importance to the immune defense by forming neutrophil extracellular traps (NETs), which cause ductal obstruction, premature trypsinogen activation, and modulate inflammation. In this review, we discuss the latest advances in understanding the pathological role of DAMPs and NETs in AP and shed light on the flexible crosstalk between these vital inflammatory mediators. We, then highlight the potentially promising treatment for AP targeting DAMPs and NETs, with a focus on novel insights into the mechanism, diagnosis, and management of AP.

Keywords: DAMPs (damage-associated molecular patterns); HMGB1 (high mobility group box 1); HSP (heat shock protein); NETs (neutrophil extracellular traps); acute pancreatitis (AP); histone.

Figure 1

HMGB1 could be released by acinar cells and other cells in both active and passive ways. It participates in the formation of NETs and induce other acinar cell necrosis to boost the inflammation, therefore enhance the pathological process of AP. Meanwhile, HMGB1 is involved in lung and intestinal injury secondary to AP and serves as a pain mediator.

Figure 2

DNA mediated inflammation via DAMPs receptors and STING signaling. Double-stranded DNA and DNA fragments were released from dying acinar cells. DsDNA activated the NF-KB and MAPK pathway through toll-like receptors to induce AP-associated inflammation. DNA fragments worsen AP-associated inflammation through STING signaling pathway in macrophages.

Figure 3

Proposed immunopathological roles of circulating histones in acute pancreatitis. DAMPs activate innate immune cells (neutrophils and macrophages) and endothelial cells through PRRs, triggering highly inflammatory programmed cell death such as neutrophil extracellular traps, necroptosis and necrosis. Extracellular histones mediate inflammation response, organ injury and death through TLR and NLRP3 inflammasome pathways.

Figure 4

Extracellular CIRP (eCIRP) is released to the extracellular space via necrosis or lysozyme extracellular pathway, afterward binds to the TLR4-MD2 receptor complex on macrophages, activates the TLR4/MyD88/NF-κB pathway and induces macrophages to release pro-inflammatory cytokines (TNF-A, IL-6, Il-1b), chemokines (keratinocyte chemical attractor and MIP-2), and HMGB1. This pathway also promotes mitochondrial DNA damage and degradation, leading to STING activation, which leads to the production of type I IFN and pro-inflammatory cytokines.

Figure 5

The intracellular DAMPs is released to the outside of the cell and can recognize PRR on surrounding neutrophils, and in turn, activate PAD4 to promote NET formation. NETs components, such as DNA and H3 histones, can further activate macrophages and endothelial cells, releasing more DAMPs out of the cell to amplify the inflammatory cascade.