Abstract
Acute pancreatitis (AP) is characterized by disordered inflammation of the pancreas, and the underlying mechanisms remain unclear. Purinergic signaling plays crucial roles in initiating and amplifying inflammatory signals. Recent evidence reveals that targeting dysregulated purinergic signaling is promising for treating inflammation-associated diseases. To explore the potential involvement of purinergic signaling in AP, we investigated the expression profiles of purinergic signaling molecules in human and mouse pancreas tissues. Results showed that purinergic receptor P2RX1 was among the most highly expressed genes in both human and mouse pancreas tissues. Genetic ablation or specific antagonism of P2RX1 markedly alleviated inflammatory responses in caerulein-induced AP mice. Bone marrow chimeras and adoptive transfer studies revealed that neutrophil-derived P2RX1 contributed to the inflammatory responses in AP. Further studies demonstrated that P2RX1 promoted neutrophil activation by facilitating glycolytic metabolism. Therefore, our study indicates that purinergic receptor P2RX1 may be a potential therapeutic target to treat disordered inflammation in AP.
Highlights
Acute pancreatitis (AP) is a necroinflammatory disease of pancreas tissues, which is associated with a mortality rate of 20% in its severe form [1]
We found that the expression profiles of purinergic signaling molecules were quite similar in the two databases
Results showed that most nucleotides release channels, ectonucleotidases, and purinergic receptors could be detected in pancreas tissues (Figure 1A), indicating that purinergic signaling was functional in pancreas tissues
Summary
Acute pancreatitis (AP) is a necroinflammatory disease of pancreas tissues, which is associated with a mortality rate of 20% in its severe form [1]. The etiological factors involved in the initiation and aggravation of disordered inflammation in AP are poorly understood [3, 4]. Efforts to understand the pathogenesis and develop novel strategies to attenuate the disease severity are imperative. Neutrophils are the most abundant immune cells in the human blood. In the early phase of AP, neutrophils are considered as the first responder cells which are recruited to pancreas tissues and contribute to the initiation of disordered inflammation [5]. Targeting neutrophils by cell depletion strategy was shown to improve the prognosis of AP in a murine model [6].
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