Activated regulatory T-cells promote duodenal bacterial translocation into necrotic areas in severe acute pancreatitis

Abstract

ObjectiveIn acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the Treg/Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP.DesignAP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (Treg) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed Tregactivation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing.ResultsThe prophylactic Treg-depletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8+/γδTCR+IELs. Tregdepleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxaEscherichia/Shigellawhich associates with severe disease and infected necrosis was diminished in Tregdepleted animals.ConclusionTregsplay a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, Treg-activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting Tregsin AP may help to ameliorate the disease course.

CTM2‐2023‐06‐1111: Targeting regulatory T‐cells in pancreas during acute pancreatitis: Programmed‐death 1 blockage as a potential therapeutic for infectious pancreatic necrosis

“…Intriguingly, most of the GFP-marked bacteria were observed in the pancreatic duct or out of the pancreatic parenchyma in the 9 h group (9H) and they were dispersed in pancreatic parenchyma in 21 h group (21H), accompanied by the significant upregulated level of Treg and PD-1 positive Treg (Figure 2B,C). Combined with the potential function of Treg reported by Glaubitz et al, 6 we hypothesized pancreatic PD-1 expression and Treg facilitate the translocation of commensal bacteria into pancreatic necrosis. Then, we used PD-1 antibody on a mouse model after 12 h to detect whether PD-1 blockage therapy could reverse the bacteria translocation.…”

“…The depletion of Tregs could decrease the bacterial translocation into pancreatic necrosis and targeting Tregs in acute pancreatitis (AP) may help to ameliorate the disease course. 1 Here, we would like to highlight the important role of Programmed-death 1+ (PD-1+) pancreatic Tregs in infectious pancreatic necrosis after acute pancreatitis and propose a new potential therapeutic method through PD-1 blockage.…”

“…Overall, inspired by the recent study related to Treg in acute pancreatitis and infectious pancreatic necrosis, 1 we preliminarily further explored the expression level of Treg, put forward a novel mouse model of infectious pancreatic necrosis for the first time, and probe the potential therapeutic efficacy of PD-1 blockage treatment in infectious pancreatic necrosis and the change in Treg. Our current data reveals the significant role of pancreatic Treg and PD-1+ Treg in promoting translocation of commensal bacteria into pancreatic necrosis, PD-1 blockage could be a novel therapeutic strategy for infectious pancreatic necrosis after acute pancreatitis.…”

“…Hua Yin 2,# Chang Wu 1,# Shiyu Li 1 Ghulam Nabi 3 Lisi Peng 1 Xiaotong Mao 1 Zhendong Jin 1 Zhaoshen Li 1 Xiaoju Su 1 Haojie Huang 1…”

The relationship between inflammatory cytokines and in‐hospital complications of acute pancreatitis

“…The uncontrolled activation of inflammatory signals and the intense release of inflammatory cytokines resulted in the severity of the patients 15 . Researchers have found that inflammation can spread from the local pancreas to nearby tissues, or cause systemic inflammation through the cascade activation of cytokines 16–18 . In this context, We retrospectively analyzed the data of 12 serum cytokines at admission of 307 patients with AP, and further evaluated their relationship with AP severity and early complications.…”