Mast Cells in Immune-Mediated Cholangitis and Cholangiocarcinoma.

Marisol I González,Bertus Eksteen,José Luis Reyes,Danielle T Vannan,Irán Flores-Sotelo

doi:10.3390/cells11030375

Marisol I González, Bertus Eksteen + Show 3 more

Open Access

https://doi.org/10.3390/cells11030375

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Abstract

Cholestasis, which is impaired bile flow from the liver into the intestine, can be caused by cholangitis and/or bile duct obstruction. Cholangitis can arise from bacterial infections and cholelithiasis, however, immune-mediated cholangitis in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) is characterized by a strong immune response targeting the biliary epithelial cells (BECs). Persistent biliary inflammation further represents a risk for biliary neoplasia, cholangiocarcinoma (CCA) by driving chronic cellular stress in the BECs. Currently, immune-mediated cholangitis is considered a Th1-Th17-dominant disease, however, the presence of Th2-related mast cells (MCs) in tissue samples from PBC, PSC and CCA patients has been described, showing that these MCs are active players in these diseases. Here, we reviewed and discussed experimental and clinical data supporting a pro-fibrotic role for MCs in immune-mediated cholangitis as well as their participation in supporting tumor growth acting as angiogenesis promoters. Thus, although MCs have classically been identified as downstream effectors of Th2 responses in allergies and parasitic infections, evidence suggests that these MCs are relevant players in biliary inflammation and neoplasia. The availability of strategies to prevent MCs’ activation represents a therapeutic opportunity in biliary diseases.

Highlights

mast cells (MCs) are able to regulate their enzyme expression in a highly dynamic manner depending on the phase of infection in the same tissue [5] and specific stimuli, such as helminthic parasites which trigger massive MC expansion [6]
In terms of MC response, these cells are activated by immune complexes, complement products (C3a and C5a), ligation of pattern recognition receptors (PRRs) on their surface and interestingly, these cells are activated by venoms from poisonous animals
Pioneer studies reported MCs residing in low numbers in the human liver [11] and it is known that MCs are found in periportal spaces [12], beneath the biliary epithelial cells (BECs) [13] and surrounding the sinusoids [14]

Summary

Mast Cells in Immune-Mediated Cholangitis

Immune-mediated cholangitis in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) is characterized as a sustained inflammatory response targeting the biliary epithelial cells (BECs) causing an initial disarrangement and subsequent narrowing of the bile ducts due to fibrotic remodeling. TGFβ which induces a profibrotic program in HSCs (i.e., alpha smooth muscle actin, αSMA induction) [45] These observations suggest that a crosstalk between BECs and MCs in chronic PBC and PSC may be inducing fibroblast and HSCs activation causing fibrotic reactions. When MCs were inhibited with cromolyn sodium, a significant decrease in biliary injury, cholangiocyte proliferation and collagen deposition was observed The latter was associated with lower MC numbers and circulating histamine levels [44]. The same research group described that, amongst other mechanisms, the FDA approved treatment for cholestatic diseases ursodeoxycholic acid (UDCA) attenuates MC infiltration, fibrosis, and histamine secretion [43] In these studies, using samples from PSC patients complemented the mouse results, providing evidence that controlling MC activity is part of the immune cholangitis treatment highlighting the relevance of these cells.

Immune Cholangitis Treatment Targets Mast Cells

Mast Cells in Cholangiocarcinoma

Conclusions