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Correspondence to Dr Aida Habtezion, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; [email protected]
Significance of this study
What is already known on this subject?
Recurrent acute pancreatitis can lead to chronic pancreatitis, and there are currently no active therapies for chronic pancreatitis.
Stimulator of interferon genes (STING) activation worsens acute pancreatitis, but its role in chronic pancreatitis is not known.
Macrophages have the ability to sense pancreatic acinar cell death and produce proinflammatory cytokines.
What are the new findings?
Unlike in acute pancreatitis, we found that STING signalling is protective in chronic pancreatitis and limits fibrosis.
We found this protection to be associated with alteration in adaptive immunity with a decrease in IL-17A+ cells in the pancreas.
STING deficiency–mediated worsening of chronic pancreatitis could be reversed with IL-17A neutralisation.
STING deficiency leads to augmented Th17 polarisation, whereas STING activation restricts Th17 generation.
Pancreatic stellate cells express functional IL-17 receptor and respond to IL-17A by activating ERK1/2 and upregulating fibrosis genes.
How might it impact on clinical practice in the foreseeable future?
We found that STING signalling is important in regulating adaptive immune responses and limiting inflammation during chronic pancreatitis. IL-17A+ cells are increased in human chronic pancreatitis tissues. Activation of STING using a pharmacological agent reduces experimental chronic pancreatitis, and this provides a novel therapeutic target.
Introduction
Chronic pancreatitis (CP) is described as progressive severe fibroinflammatory condition with irreversible damage to the pancreas, characterised by acinar cell death, inflammation and fibrosis.1–3 Currently, there are no FDA-approved therapies for CP. Various animal models have been developed to understand the molecular mechanism and identify potential therapeutic targets for the disease.4 Due to its chronicity and ongoing inflammation, exploring innate and adaptive immune signals during CP offers potential means of altering the natural course of the disease with hopes of rendering it from an ‘irreversible’ to a reversible disease.
Stimulator of interferon genes (STING, encoded by TMEM173) signalling can sense abnormal DNA or cyclic dinucleotides in the cytosol of cells, as well as extracellular self DNA caused by apoptosis or necrosis, and bacterial or viral DNA.5–9 STING signalling activation leads to induction of type I interferons (IFNs) and proinflammatory cytokines. Recently, we...