STING signalling protects against chronic pancreatitis by modulating Th17 response

Area of Science:

• Immunology
• Gastroenterology
• Pathology

Background:

• Chronic pancreatitis (CP) is an inflammatory condition with progressive fibrosis and no effective therapies.
• Stimulator of interferon genes (STING) signalling is a key innate immune sensor of DNA involved in immune responses.

Purpose of the Study:

• To evaluate the role of STING signalling in the pathogenesis of chronic pancreatitis.
• To investigate STING's therapeutic potential for CP.

Main Methods:

• Used a mouse model of CP with STING wild-type and knockout mice, and bone marrow chimeras.
• Administered a STING agonist and anti-IL-17A antibodies.
• Analyzed immune cell infiltration (Th17), cytokine levels (IL-17A), and pancreatic stellate cell activation.
• Examined human pancreatic tissue from CP patients.

Main Results:

• STING activation reduced pancreatic inflammation and fibrosis in experimental CP.
• STING deficiency exacerbated CP, correlating with increased Th17 cell infiltration.
• Anti-IL-17A antibody treatment ameliorated CP severity in STING-deficient mice.
• Pancreatic stellate cells express IL-17 receptor and upregulate fibrosis genes upon IL-17A stimulation.
• Human CP tissues showed increased IL-17A+ cells compared to controls.

Conclusions:

• STING activation is protective in chronic pancreatitis, contrasting with its role in acute pancreatitis.
• STING signalling modulates adaptive immunity by suppressing IL-17A generation in CP.
• Targeting STING signalling represents a novel therapeutic strategy for chronic pancreatitis.