TWEAK/Fn14 Signalling Regulates the Tissue Microenvironment in Chronic Pancreatitis

Simple Summary The TWEAK/Fn14 signalling pathway has emerged as a major regulator of tissue injury and regeneration through its pro-proliferative, pro-inflammatory, and pro-fibrotic cellular effects. Its role in pancreatic injury and cancer has not been elucidated. In this study, we confirmed the choline-deficient, ethionine-supplemented diet as a suitable murine model to study chronic pancreatitis and demonstrated that TWEAK/Fn14 signalling plays a significant role in the establishment and progression of the chronic pancreatitis tissue microenvironment. Chronic pancreatitis increases the risk of developing pancreatic cancer through the upregulation of pathways favouring proliferation, fibrosis, and sustained inflammation. We established in previous studies that the ligand tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signals through its cognate receptor fibroblast growth factor-inducible 14 (Fn14) to regulate these underlying cellular processes in the chronic liver injury niche. However, the role of the TWEAK/Fn14 signalling pathway in pancreatic disease is entirely unknown. An analysis of publicly available datasets demonstrated that the TWEAK receptor Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, with single cell RNA sequencing revealing pancreatic ductal cells as the main Fn14 producers. We then used choline-deficient, ethionine-supplemented (CDE) diet feeding of wildtype C57BL/6J and Fn14 knockout littermates to (a) confirm CDE treatment as a suitable model of chronic pancreatitis and (b) to investigate the role of the TWEAK/Fn14 signalling pathway in pancreatic ductal proliferation, as well as fibrotic and inflammatory cell dynamics. Our time course data obtained at three days, three months, and six months of CDE treatment reveal that a lack of TWEAK/Fn14 signalling significantly inhibits the establishment and progression of the tissue microenvironment in CDE-induced chronic pancreatitis, thus proposing the TWEAK/Fn14 pathway as a novel therapeutic target.