Abstract | OBJECTIVE:
Chronic pancreatitis (CP) is an inflammatory disease with progressive fibrosis leading to exocrine and endocrine dysfunction. Currently, there are no approved effective therapies for CP. Stimulator of interferon genes ( STING) signalling is a key innate immune sensor of DNA. In this study, we evaluated the role of STING signalling in CP. DESIGN: We used an experimental model of CP to test the effect of STING signalling in STING wild-type and knockout mice as well as bone marrow chimaeras (BMCs). STING was activated using a pharmacological agent. Since we found changes in Th17 cells, we used neutralising and control antibodies to determine the role of IL-17A. The effect of STING signalling was further explored in IL-17A generation and we examined the effect of IL-17A on pancreatic stellate cells (PSCs). Human pancreas from patients with CP and without CP were also stained for IL-17A. RESULTS:
STING activation decreased CP-associated pancreatic inflammation and fibrosis, whereas absence of STING led to worsening of the disease. BMCs showed that leucocytes play an important role in STING signalling-mediated amelioration of experimental CP. STING deletion was associated with increased Th17 cell infiltration in the pancreas, whereas STING agonist limited this Th17 response. Importantly, anti-IL-17A antibody treatment mitigated the severity of CP in the absence of STING signalling. STING deficiency promoted Th17 polarisation and PSCs express functional IL-17 receptor by upregulating fibrosis genes. Compared with tumour margins, pancreas from patients with CP had significant increase in IL-17A+ cells. CONCLUSION: Unlike acute pancreatitis, STING activation is protective in CP. STING signalling is important in regulating adaptive immune responses by diminishing generation of IL-17A during CP and presents a novel therapeutic target for CP.
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Authors | Qinglan Zhao, Murli Manohar, Yi Wei, Stephen J Pandol, Aida Habtezion |
Journal | Gut
(Gut)
Vol. 68
Issue 10
Pg. 1827-1837
(10 2019)
ISSN: 1468-3288 [Electronic] England |
PMID | 30705050
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. |
Chemical References |
- Membrane Proteins
- Sting1 protein, mouse
- DNA
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Topics |
- Animals
- Blotting, Western
- Cells, Cultured
- Chronic Disease
- DNA
(genetics)
- Disease Models, Animal
- Gene Expression Regulation
- Humans
- Immunity, Cellular
(genetics)
- Immunohistochemistry
- Membrane Proteins
(genetics)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Pancreatitis
(immunology, metabolism, pathology)
- Polymerase Chain Reaction
- Signal Transduction
- Th17 Cells
(immunology, metabolism)
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