Mucin-1 is required for Coxsackie Virus B3-induced inflammation in pancreatitis

Abstract

The Muc-1 oncoprotein is a tumor-associated mucin often overexpressed in pancreatic cancer. We report that knockout of Muc-1 reduced the degree of pancreatic inflammation that resulted from infection with Coxsackievirus B3 (CVB3) in a mouse model. CVB3-infected Muc-1-deficient (Muc-1 KO ) mice had significantly reduced infiltration of macrophages into the murine pancreas. We found that Muc-1 signaling through NF-κB increased expression of ICAM-1, a pro-inflammatory mediator that recruits macrophages. Further investigation revealed that bone marrow derived macrophages (BMDM) from the Muc-1 KO mice exhibited defective migration properties, in part due to low expression of the C-C motif chemokine receptor (CCR2) and the integrin Very Late Antigen 4 (VLA-4). The results presented here provide novel insight into the role of Muc-1 in regulating the inflammatory response and the cellular microenvironment in pancreatitis.

MUC1-mediated Macrophage Activation Promotes Colitis-associated Colorectal Cancer via Activating the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Axis

“…55,56 The cell surface MUC1 extracellular domain expressed on leukocytes has also been demonstrated to mediate trans-endothelial cellular migration of Mɸs by binding to endothelial ICAM-1, 57,58 partly by instigating Src-CrlL-Rac1/Cdc42 facilitated actin cytoskeletal protrusive motility. 59,60 Although a lower level of ICAM-1 expression in the Muc1 deficient pancreas leads to reduction of infiltration of Mɸs in a coxsackie virus B3infection model, 61 we did not observe a difference of expression of Icam1 between WT and Muc1 deficient colonic tissues during AOM/DSS treatment.…”

“…Our findings are supported by a recent investigation showing Muc1 -deficient BMDMs had reduced Ccr2 expression, resulting in decreased LPS-induced migration in a coxsackie virus B3-infection model. 61 Thus, our results suggest that MUC1 contributes to colonic tissue Mɸ infiltration by enhancing both epithelial and Mɸ CCL2 production and by promoting Mɸ migration responses to CCL2.…”

Lactiplantibacillus plantarum attenuates Coxsackievirus B3-induced pancreatitis through the BAX/BCL2/CASP3 signaling pathway

“…Much research has shown that abundant neutrophils and macrophages are produced and recruited into the mouse pancreas during early CVB3 infection, secreting various cytokines, including IL-1β, IL-6, and TNF-α. 11,35 Then, massive acinar cell destruction is seen in the pancreas of mice, which develop acute pancreatitis. 36 In addition, CVB3 infection is known to induce cellular apoptosis.…”

“…6,7 CVB3 may spread from the intestinal tract to internal organs such as the pancreas and heart, causing pancreatitis 8 and myocarditis 9,10 ranging from mild to severe, including acute and chronic inflammation. 11,12 However, there remain no efficient vaccines or antivirals for treating pancreatitis caused by CVB3, highlighting the need for investigating new strategies to treat pancreas lesions.…”

The potential roles of exosomes in pancreatic cancer initiation and metastasis

“…However its physiological significance remains to be verified. Many viruses, including hepatitis viruses [ 77 ], human immunodeficiency virus [ 78 ], epstein-barr virus, [ 79 ] and coxsackie virus [ 80 ], can also cause pancreatitis. Among these viruses, coxsackie virus B3 (CVB3) infection has been reported to induce an increase on the levels of intracellular Ca 2+ as well as cytoskeleton depolymerization in host cells, promoting the secretion of CVB3-positive exosomes that may propagate virus transmission upon uptake by non-infected cells.…”