Neutrophil extracellular traps (NETs) are produced in large quantities at the site of inflammation, and they locally capture and eliminate various pathogens. Thus, NETs quickly control the infection of pathogens in the body and play vital roles in immunity and antibacterial effects. However, evidence is accumulating that NET formation can exacerbate pancreatic tissue damage during acute pancreatitis (AP). In this review, we describe the research progress on NETs in AP and discuss the possibility of NETs as potential therapeutic targets. In addition, since the current detection and visualization methods of NET formation are not uniform and the selection of markers is still controversial, a synopsis of these issues is provided in this review.
Neutrophil extracellular traps (NETs) promote intra‐acinar trypsin activation and tissue damage. Therefore, reducing NET formation can reduce tissue damage in severe acute pancreatitis (SAP). However, NET formation pathways may differ among disease models. In this study, we evaluated the role of the myeloperoxidase–neutrophil elastase (NE) pathway in NET formation in SAP. SAP was induced by intraperitoneal injection of cerulein and LPSs in mice, and NE activity was inhibited by GW311616. Pancreatic tissues were collected for multiplex immunofluorescence, scanning electron microscopy, and western blotting to detect NET formation and the effect of NE on citrullinated histone H3, followed by analyses of serum amylase and cytokine levels. Pretreatment with GW311616 significantly reduced NET formation, pancreatic tissue damage, and systemic inflammatory responses in SAP. Network pharmacology analyses using NE as the target revealed the monomeric compound epigallocatechin‐3‐gallate (EGCG). Binding between EGCG and NE was validated using molecular docking, and the ability of EGCG to inhibit NE activity was verified experimentally. NET formation by PMA‐stimulated neutrophils was significantly reduced in vitro when the cells were pretreated with 40 μM EGCG. Pretreatment with EGCG significantly reduced NET formation, pancreatic tissue damage, and systemic inflammatory responses in vivo. These results reveal that NET formation requires the myeloperoxidase‐NE pathway, and citrullination of histone H3 is affected by NE activity in SAP. EGCG shows therapeutic potential for affecting NE activity, NET formation, and systemic inflammation in SAP.
Immunotherapies that were developed based on our understandings of tumor immunology have revolutionized cancer treatment. However, the success of immunotherapy is eclipsed by several grand challenges, including low response rate, intrinsic/acquired resistance and adverse effects. While a deeper understanding of the interaction between tumor and our immune system, especially the tumor immune niche, is essential to overcome those challenges, we are limited by the fact that most of our knowledge about tumor immunology is based on studies analyzing bulk populations of cells, which are often unable to fully characterize the various cell types and states engaged in immune cell functions. The advent of cutting single‐cell genomic technologies empowers us to dissect the tumor immune niche in a genome‐wide and spatially resolved manner in single cells, trace their clonal histories, and unveil their regulatory circuits. Future studies on tumor immunology in the age of single‐cell genomics, therefore, hold the promise to develop more effective and precise immunotherapies for human cancers. In this perspective, we will discuss how advanced single‐cell genomics approaches will revolutionize tumor immunology research and immunotherapies by catering the demand in the field of tumor immunology.
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