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Title: | Ductular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver disease |
Author: | Ariño, Silvia Aguilar Bravo, Beatriz Coll, Mar Lee, Woo-Yong Peiseler, Moritz Cantallops Vilà, Paula Sererols Viñas, Laura Martínez-García de la Torre, Raquel Martínez-Sánchez, Celia Pedragosa, Jordi Zanatto, Laura Gratacós Ginès, Jordi Pose, Elisa Blaya, Delia Almodóvar, Xènia Fernández-Fernández, María Ruiz-Blázquez, Paloma Lozano Salvatella, Juan José Affò, Silvia Planas, Anna M. Ginès i Gibert, Pere Moles, Anna Kubes, Paul Sancho Bru, Pau |
Keywords: | Neutròfils Cèl·lules epitelials Malalties del fetge Cròniques Neutrophils Epithelial cells Liver diseases Chronicles |
Issue Date: | 1-Jun-2023 |
Publisher: | Elsevier |
Abstract: | Background & aims: Ductular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are largely unknown. Here, we identify neutrophils as drivers of biliary cell proliferation and the defective wound-healing response. Methods: The intrahepatic localization of neutrophils was evaluated in patients with chronic liver disease. Neutrophil dynamics were analyzed by intravital microscopy and neutrophil-labeling assays in DDC-treated mice. Neutrophil depletion or inhibition of recruitment was achieved using a Ly6g antibody or a CXCR1/2 inhibitor, respectively. Mice deficient in PAD4 (peptidyl arginine deiminase 4) and ELANE/NE (neutrophil elastase) were used to investigate the mechanisms underlying ductular reaction expansion. Results: In this study we describe a population of ductular reaction-associated neutrophils (DRANs), which are in direct contact with biliary epithelial cells in chronic liver diseases and whose numbers increased in parallel with disease progression. We show that DRANs are immobilized at the site of ductular reaction for a prolonged period of time. In addition, liver neutrophils display a unique phenotypic and transcriptomic profile, showing a decreased phagocytic capacity and increased oxidative burst. Depletion of neutrophils or inhibition of their recruitment reduces DRANs and the expansion of ductular reaction, while mitigating liver fibrosis and angiogenesis. Mechanistically, neutrophils deficient in PAD4 and ELANE abrogate neutrophil-induced biliary cell proliferation, thus indicating the role of neutrophil extracellular traps and elastase release in ductular reaction expansion. Conclusions: Overall, our study reveals the accumulation of DRANs as a hallmark of advanced liver disease and a potential therapeutic target to mitigate ductular reaction and the maladaptive wound-healing response. Impact and implications: Our results indicate that neutrophils are highly plastic and can have an extended lifespan. Moreover, we identify a new role of neutrophils as triggers of expansion of the biliary epithelium. Overall, the results of this study indicate that ductular reaction-associated neutrophils (or DRANs) are new players in the maladaptive tissue-healing response in chronic liver injury and may be a potential target for therapeutic interventions to reduce ductular reaction expansion and promote tissue repair in advanced liver disease. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1016/j.jhep.2023.05.045 |
It is part of: | Journal of Hepatology, 2023 |
URI: | http://hdl.handle.net/2445/206302 |
Related resource: | https://doi.org/10.1016/j.jhep.2023.05.045 |
DOI: | 10.1016/j.jhep.2023.05.045 |
ISSN: | 0168-8278 |
Appears in Collections: | Articles publicats en revistes (Medicina) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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Document embargat fins el 31-10-2024
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