Extracellular vesicles and pancreatitis: mechanisms, status and perspectives

Abstract

Comprehensive reviews and large population-based cohort studies have played an important role in the diagnosis and treatment of pancreatitis and its sequelae. The incidence and mortality of pancreatitis have been reduced significantly due to substantial advancements in the pathophysiological mechanisms and clinically effective treatments. The study of extracellular vesicles (EVs) has the potential to identify cell-to-cell communication in diseases such as pancreatitis. Exosomes are a subset of EVs with an average diameter of 50~150 nm. Their diverse and unique constituents include nucleic acids, proteins, and lipids, which can be transferred to trigger phenotypic changes of recipient cells. In recent years, many reports have indicated the role of EVs in pancreatitis, including acute pancreatitis, chronic pancreatitis and autoimmune pancreatitis, suggesting their potential influence on the development and progression of pancreatitis. Plasma exosomes of acute pancreatitis can effectively reach the alveolar cavity and activate alveolar macrophages to cause acute lung injury. Furthermore, upregulated exosomal miRNAs can be used as biomarkers for acute pancreatitis. Here, we summarized the current understanding of EVs in pancreatitis with an emphasis on their biological roles and their potential use as diagnostic biomarkers and therapeutic agents for this disease.

Keywords: biomarkers; exosomes; extracellular vesicles; pancreatitis.

Figure 1

The role of extracellular vesicles in the mechanism of AP-related alveolar macrophage activation. The figure shows that in vitro experiments (left) revealed that part of the PAAF exosomes released from the pancreas during AP entered the liver directly through the portal system, and most of them were retained in liver tissue. During AP, the formation of new circulating exosomes from the liver reached the alveoli and activated the alveolar macrophages from the M2 phenotype to the pro-inflammatory M1 phenotype, leading to significantly increased expression of cytokines IL-1, IL-6 and chemokine CCL2, while the expression of MRC1 and CD36 was decreased. In vivo experiments (right) showed that plasma exosomes from AP promoted the activation of alveolar macrophages from the M2 phenotype to the pro-inflammatory M1 phenotype, and resulted in significantly increased expression of the inflammatory cytokines IL-1 and the chemokine CCL2 in alveolar macrophages.

Figure 2

The expression of pro-inflammatory miR-155 in plasma exosomes produced during AP was significantly increased, while the expressions of anti-inflammatory miR-122 and miR-21 were decreased. The arrival of plasma exosomes to the alveoli and by activating alveolar macrophages leads to increased expression of the inflammatory cytokines IL-1 and the chemokines CCL2 and CXCL1, thus exacerbating AP-related lung injury. In addition, PAAF exosomes produced during AP contain more histones, which induce inflammation by regulating the transcription of non-coding RNA to produce TERRA.

Figure 3

AP-generated plasma exosomes activate NLRP3 inflammasomes in alveolar macrophages and induce NLRP3-dependent pyroptosis, leading to apoptosis in alveolar macrophages and increased expression of the inflammatory cytokine IL-1.

Figure 4

Overexpression of Klotho protein in exosomes from genetically engineered mesenchymal stem cells can reduce the inflammatory response of pancreatic acinar cells (AR42J cells) in the model of acute pancreatitis induced by caerulein.

Figure 5

Role of extracellular vesicles in CP - associated pancreatic fibrosis. The figure shows that in activated PSC in alcoholic chronic pancreatitis, up-regulated CCN2 and miR-21 constitute a positive feedback pathway that promotes collagen α1 production. In addition, exosomes produced by activated PSCs contained CCN2 and miR-21, and these exosomes could activate more PSCs and produce more exosomes and collagen α1.