Abstract
Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer. Chronic pancreatitis (CP) is a fibro-inflammatory disease in which recurrent pancreatic inflammation leads to pancreatic fibrosis. In the present study, we have investigated the role of DDR1 and DDR2 in CP. The induced expression of DDR1 and DDR2 was observed in primary pancreatic stellate cells (PSCs) and cerulein-induced CP. Subsequently, the protective effects of DDR1/DDR2 inhibitor, imatinib (IMT) were investigated. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, IMT treatment reduced pancreatic injury, inflammation, extracellular matrix deposition and PSCs activation along with inhibition of TGF-β1/Smad signaling pathway. Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic inflammation and fibrosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP.
Highlights
Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer
These results indicated the upregulation of DDR1 and DDR2 receptors in the progression of Chronic pancreatitis (CP) and associated pancreatic fibrosis
Our results demonstrated that transforming growth factor (TGF)-β1treated pancreatic stellate cells (PSCs) showed notably upregulated pDDR1, DDR2 and collagen1a expression and the expression of these proteins was markedly inhibited by IMT treatment (Fig. 3F,G)
Summary
Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer. IMT treatment reduced pancreatic injury, inflammation, extracellular matrix deposition and PSCs activation along with inhibition of TGF-β1/Smad signaling pathway. Inflammatory mediators and excessive synthesis of ECM proteins such as collagen I, III and fibronectin[4] Among these mediators, transforming growth factor (TGF)-β1 is the potent profibrotic cytokine which regulates PSCs activation and pancreatic fibrogenesis through its downstream Smad signaling p athway[5]. DDR1 is majorly expressed in epithelial cells and activated by both fibrillar and nonfibrillar collagens (type I to V, VIII, and XI), while DDR2 is expressed in fibroblasts and activated by fibrillar collagens (type I and III) This binding causes phosphorylation and dimerization of the tyrosine kinase receptors which leads to the activation of different signaling pathways involved in inflammation and fibrosis[7]. The DDRs are involved in inflammatory and fibrotic diseases but their role in CP and associated fibrosis is not explored fully
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