Targeting neutrophil extracellular traps in severe acute pancreatitis treatment

Abstract

Severe acute pancreatitis (SAP) is a critical abdominal disease associated with high death rates. A systemic inflammatory response promotes disease progression, resulting in multiple organ dysfunction. The functions of neutrophils in the pathology of SAP have been presumed traditionally to be activation of chemokine and cytokine cascades accompanying the inflammatory process. Recently, since their discovery, a new type of antimicrobial mechanism, neutrophil extracellular traps (NETs), and their role in SAP, has attracted widespread attention from the scientific community. Significantly different from phagocytosis and degranulation, NETs kill extracellular microorganisms by releasing DNA fibers decorated with granular proteins. In addition to their strong antimicrobial functions, NETs participate in the pathophysiological process of many noninfectious diseases. In SAP, NETs injure normal tissues under inflammatory stress, which is associated with the activation of inflammatory cells, to cause an inflammatory cascade, and SAP products also trigger NET formation. Thus, due to the interaction between NET generation and SAP, a treatment targeting NETs might become a key point in SAP therapy. In this review, we summarize the mechanism of NETs in protecting the host from pathogen invasion, the stimulus that triggers NET formation, organ injury associated with SAP involving NETs, methods to interrupt the harmful effects of NETs, and different therapeutic strategies to preserve the organ function of patients with SAP by targeting NETs.

Keywords: NETs formation; SAP; intervention; neutrophil extracellular traps; tissue damage.

Figure 1.

Molecular signaling pathway underlying NETs formation induced by different stimulus. PMA binds to PKC on the cell membrane to activate the Raf-MEK-ERK signaling pathway cascade and NOX, resulting in the production of ROS. ROS act as initiators of the azurosome to liberate NE from the protein complex composed of MPO, NE, and cathepsin G, among other granular proteins. After NE translocation to the nucleus, the core histones are proteolyzed, resulting in decondensation of the chromatin. Calcium ionophores can activate PAD4 directly and induce NETs release without ROS generation. III. After activated by LPS, GPIb on the surface of platelets can bind to CD18 on neutrophils, then activate Src kinase-PI3K-ERK pathway, resulting in proliferation. CD18, β2-integrin; GPIb, glycoprotein Ib; LPS, lipopolysaccharide; MPO, myeloperoxidase; NE, neutrophil elastase; NETs, neutrophil extracellular traps; NOX, NADPH oxidase; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; ROS, reactive oxygen species.

Figure 2.

NETs formation stimulated by different stimulus have different DNA sources and destiny. (A) Nuclear source: after triggering by some stimuli such as Staphylococcus aureus, PMNs first lose their nuclear lobules; the nuclear membrane then ruptures and forms vesicles containing DNA and protein. After transfer of these vesicles to the cell membrane, they fuse with the cell membrane and release the complex of DNA and protein, which is called vital NETosis. This phenomenon often occurs in the early period of the reaction (30–60 min). With increasing reaction time, more NETs will be released from the cell, the nuclear membrane will gradually dissolve, a large amount of DNA will be depolymerized, and the expansion force formed will rupture the cell membrane and eventually cause cell death: so-called suicide NETosis. However, when PMNs are stimulated by PMA, the cells break down directly after lobule disappearance and NET release. (B) Mitochondrial source: after stimulation by LPS or C5a, mitochondria translocate to the cell membrane, and DNA is released from the cell to form NETs without the occurrence of nuclear and membrane lysis, which is another type of vital NETosis. LPS, lipopolysaccharide; NETs, neutrophil extracellular traps; PMA, phorbol 12-myristate 13-acetate; PMNs, polymorphonuclear leukocytes.

Figure 3.

NETs damage in the pancreas. During SAP, neutrophils are transferred to the pancreatic acinus by inflammatory chemotaxis and stimulated by various factors to form NETs. In addition to injuring acinar cells directly, NETs can entwine one another to form aggNETs, which can lead to occlusion of pancreatic duct aggravating SAP. NETs can also trigger thrombosis in intralobular artery and cause pancreatic lobular ischemia and necrosis. aggNETs, aggregates of NETs; NETs, neutrophil extracellular traps; SAP, severe acute pancreatitis.

Figure 4.

NETs damage in the lung and kidney. Left: NETs release due to inflammatory factor stimulation in the alveolar space. When the barrier formed by epithelial cells is destroyed, the alveolar mucosa and capillary permeability increase, and cells in blood translocate into the alveolar space. PMNs release NETs when stimulated by inflammatory factors or pathogens. After NETs formation, the toxic proteins in turn damage the epithelium and endothelium, even triggering NETs generation and NET-derived thrombosis in the vasculature. Right: The components of NETs can trigger inflammatory injury to glomerular vessels and podocytes, affecting glomerular filtration functions; conversely, NETs components can lead to tubular epithelial cell death and reabsorption dysfunction. NETs, neutrophil extracellular traps; PMNs, polymorphonuclear leukocytes.

Figure 5.

Intervention targets for NETs mitigate the severity of SAP. (A) NETs and their components, like poisonous arrows, cause devastating blows to tissues under SAP inflammation stress, leading to lethal complications of SAP, such as acute lung injury, acute kidney injury, myocardial injury, and intestinal dysfunction. Furthermore, NETs can be induced by components of the pancreatic juice or inflammatory factors released in SAP, and they also act as inducers of SAP via pancreatic acinar injury or blockade of the pancreatic duct. The generation of NETs and SAP seem to form a vicious circle. (B) Three kinds of interventions that target NETs can effectively decrease inflammatory injury in tissue (halt the threatening arrows) to disrupt the NET-SAP loop and protect organ function. NETs, neutrophil extracellular traps; PMN, polymorphonuclear leukocyte; SAP, severe acute pancreatitis.