c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis

Abstract

Neutrophil extracellular traps (NETs) are involved in acute pancreatitis (AP) but mechanisms controlling NET expulsion in AP are incompletely understood. Herein, we examined the role of c‐Abelson (c‐Abl) kinase in NET formation and tissue damage in severe AP. AP was induced by taurocholate infusion into pancreatic duct or intraperitoneal administration of l‐arginine in mice. Pancreatic, lung, and blood samples were collected and levels of phosphorylated c‐Abl kinase, citrullinated histone 3, DNA‐histone complexes, myeloperoxidase, amylase, cytokines, and CXC chemokines were quantified. Citrullinated histone 3, reactive oxygen species (ROS), and NET formation were determined in bone marrow neutrophils. Taurocholate challenge increased phosphorylation of c‐Abl kinase and levels of citrullinated histone 3 in the pancreas as well as DNA‐histone complexes in the plasma. Administration of the c‐Abl kinase inhibitor GZD824 not only abolished activation of c‐Abl kinase but also decreased levels of citrullinated histone 3 in the pancreas and DNA‐histone complexes in the plasma of animals with AP. Moreover, GZD824 decreased plasma levels of amylase, IL‐6, and MMP‐9 as well as edema, acinar cell necrosis, hemorrhage, CXC chemokine formation, and neutrophil infiltration in the inflamed pancreas. A beneficial effect of c‐Abl kinase inhibition was confirmed in l‐arginine‐induced pancreatitis. In vitro, inhibition of c‐Abl kinase reduced TNF‐α‐induced formation of ROS, histone 3 citrullination, and NETs in isolated bone marrow neutrophils. Our findings demonstrate that c‐Abl kinase regulates NET formation in the inflamed pancreas. In addition, inhibition of c‐Abl kinase reduced pancreatic tissue inflammation, and damage in AP. Thus, targeting c‐Abl kinase might be a useful way to protect the pancreas in severe AP.

Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling

“…In this study, we used LPS as a stimulator of inflammation to determine the effects of dasatinib on LPS-stimulated neuroinflammatory responses. Interestingly, several studies have found that the activity of the tyrosine kinase c-Abl increases LPS-induced inflammation in macrophages, BV2 microglial cells, and a mouse model of acute pancreatitis [23–25]. The Src tyrosine kinase family regulates local inflammation in colorectal cancer and LPS-induced inflammatory responses [26, 27].…”

The Role of Pancreatic Infiltrating Innate Immune Cells in Acute Pancreatitis

“…NETs were initially thought to be a mechanism by which neutrophils clear pathogens, for example, the replication of staphylococcus aureus, salmonella typhimurium, streptococcus pneumoniae, and shigella flexneri can be inhibited by NETs [30,[33][34][35]. But its critical role in sterile inflammation has also been revealed in recent years, such as deep venous thrombosis [36], lung cancer [37], arthritis [38], AP [25,39,40], endogenous particulate-related injury [41], glioma [31], liver ischemia-reperfusion injury [42], ischemic stroke [43], etc.…”

“…A substantial number of studies have suggested that neutrophils are involved in the pathogenesis of AP [25,27,28,39,40, (Figure 2). Measurements of MPO levels in serum [27] or pancreatic tissue [49,54,61] can reflect the number and activity of infiltrating neutrophils.…”

“…During AP, the pancreatic juice is a strong instigator of infiltrating neutrophil chromatin extrusion and thereby lead to the formation of macroscopic NETs aggregates, which may occlude pancreatic duct and drive pancreatic inflammation, inhibition of NETs formation can mitigate AP [57]. For the detection of NETs formation in AP, cell-free DNA (cfDNA) [55], MPO-DNA complex [55], or histone-DNA complex [39,75] in blood samples can be measured by commercial kits. Besides, citrullinated histone H3 (CitH3) [39,75] in pancreatic samples can be measured by western blot.…”

Drug discovery and formulation development for acute pancreatitis

“…The activated neutrophils also contributed to the neutrophil extracellular traps (NETS) generation, involved in the acute pancreatitis progression by worsening inflammation and promoting pancreatic duct obstruction (Murthy et al., 2019 ). C-Abelson (c-Abl), the crucial kinase in the NETS formation, might serve as a new target in the acute pancreatitis treatment, as evidenced by the beneficial effect of c-Abl kinase inhibitor (GZD824) in L-arginine-induced pancreatitis by decreasing amylase level, pro-inflammatory cytokines level, neutrophil infiltration as well as acinar cell necrosis (Madhi et al., 2019 ).…”