Plasma Exosomes Aggravate Acute Pancreatitis by Promoting M1 Polarization of Adipose Tissue Macrophages in Obesity-Related Severe Acute Pancreatitis

Abstract

Background and aims: Obesity may be a risk factor for severe acute pancreatitis (SAP). However, its precise mechanism is not yet fully understood.

Methods: We fed rats with a standard laboratory diet (SLD) and a high-fat diet (HFD). SAP model rats were established by retrograde injection of sodium taurocholate. Serum non-esterified fatty acids (NEFAs), lipase (LPS), and myeloperoxidase (MPO) were measured, as were adipose IL-1, IL-6, IL-10, and TNF-α levels. HE staining was performed to determine the severity of pancreatitis. Serum exosomes were extracted from rats with obesity-related SAP, verified by transmission electron microscopy (TEM) and western blot analysis, and co-cultured with THP-1 cells. Flow cytometry was used to analyze the M1 and M2 phenotypes of macrophages in adipose tissues and THP-1 cells. Q-PCR was used to analyze the levels of IL-1, IL-6, IL-10, and TNF-α in each group of cells.

Results: The body weight and serum NEFA concentrations of rats in the HFD group were significantly higher than those in the SLD group. Adipose tissue macrophages in the HFD group exhibited a higher percentage of the M1 type than those in the SLD group. The severity of pancreatitis were significantly increased in the HFD + SAP group. Pro-inflammatory macrophages and cytokines were significantly higher in the HFD + SAP group and THP-1 cells co-cultured with serum exosomes extracted from rats with obesity-related SAP.

Conclusions: Obesity might worsen the severity of pancreatitis by amplifying the immune response and activating M1 polarization in adipose tissue macrophages via serum exosomes in rats of obesity-related SAP. In our study, we isolated exosomes from the serum of mice with obesity-related SAP. After inducing THP-1 cells to become M0-typed macrophages, we co-cultured the cells with exosomes and observed that exosomes from obesity-related SAP increased the proportion of M1-typed macrophages and promoted the release of pro-inflammatory factors such as IL-1, IL-6, and TNF. Therefore, obesity might worsen the severity of pancreatitis by amplifying the immune response and activating M1 polarization in adipose tissue macrophages via serum exosomes in rats of obesity-related SAP.

Keywords: Adipose tissue macrophages; Exosome; Inflammasomes; Inflammation; Pancreatitis.