Role of ductular reactive cells in recruiting immune cells
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LETTER TO THE EDITOR, NEWS AND VIEWS
Role of ductular reactive cells in recruiting immune cells Ahmed Ghallab1 Received: 17 August 2020 / Accepted: 18 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
In the recent issue of Hepatology, Gores et al. from the Mayo Clinic in Rochester published an article about the role of ductular reactions recruiting immune cells to the liver and the relevance for progression of fibrosis (Azad et al. 2020). The authors used double knock-out mice for mdr2 and the TRAIL receptor (TR), a pro-apoptotic death receptor. Double knock-out mice (mdr2−/− Tr−/−) showed an abundant ductular reaction as well as severe liver fibrosis (Azad et al. 2020). Single cell transcriptomics with cells from cholangiocyte organoids revealed a cell cluster expressing relatively high levels of chemokines. In mice in vivo the authors demonstrated the presence of a heterogeneous set of immune cells, including B lymphocytes (Azad et al. 2020). Interestingly, exposure to S63845, an MCL1 inhibitor that induces apoptosis of ductular reactive cells in m dr2−/− Tr−/− mice, strongly reduced infiltration of immune cells into the liver as well as the extent of fibrosis. The authors concluded that cells from ductular reactions play a key role in recruiting immune cells to the liver and that pharmacological interventions to diminish ductular reactions may be a therapeutic option for liver fibrosis (Azad et al. 2020). In recent years, numerous research activities aimed for a better understanding of the mechanisms of liver damage (Ghallab et al. 2016, 2019a; Grinberg et al. 2014), fibrogenesis (Godoy et al. 2013, 2016; Ghallab et al. 2019b) and regeneration (Hoehme et al. 2010; Bartl et al. 2015). In the present study, Azad et al. (2020) contribute to the ongoing discussion whether diminishing ductular reactive cells represent a useful therapeutic target or not. Previous investigations reported that ductular reactions are an adaptive response to cholestasis that support the drainage of bile (Vartak et al. 2016). Bile canaliculi are functionally connected to ducts (Vartak et al. 2020) and as soon as the bile canalicular network loses its connectivity in cholestatic * Ahmed Ghallab [email protected] 1
Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
liver diseases, e.g. by reduced numbers of Hering channels, by obstructions (Vartak et al. 2016) or by fragmented canalicular networks, the newly formed ductular reactions may support the drainage of bile. It may also be discussed if the chemokines released by cholangiocytes from ductular reactions are responsible for the attraction of immune cells; an alternative mechanism may also be that the newly formed ducts are leaky and the released bile or tissue damage induced by leaking bile acids are responsible for immune cell infiltration. The authors are to be congratulated for a very valuable, technically challenging contribution to the complex and controversial discussion on the
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