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Pharmacological inhibition of P2RX7 ameliorates liver injury by reducing inflammation and fibrosis.

التفاصيل البيبلوغرافية
العنوان: Pharmacological inhibition of P2RX7 ameliorates liver injury by reducing inflammation and fibrosis.
المؤلفون: Bernat Baeza-Raja, Andrew Goodyear, Xiao Liu, Kevin Lam, Lynn Yamamoto, Yingwu Li, G Steven Dodson, Toshi Takeuchi, Tatiana Kisseleva, David A Brenner, Karim Dabbagh
المصدر: PLoS ONE, Vol 15, Iss 6, p e0234038 (2020)
بيانات النشر: Public Library of Science (PLoS), 2020.
سنة النشر: 2020
المجموعة: LCC:Medicine
LCC:Science
مصطلحات موضوعية: Medicine, Science
الوصف: Extracellular adenosine triphosphate (eATP) released by damaged cells, and its purinergic receptors, comprise a crucial signaling network after injury. Purinergic receptor P2X7 (P2RX7), a major driver of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and IL-1β processing, has been shown to play a role in liver injury in murine diet- and chemically-induced liver injury models. It is unclear, however, whether P2RX7 plays a role in non-alcoholic steatohepatitis (NASH) and which cell type is the main target of P2RX7 pharmacological inhibition. Here, we report that P2RX7 is expressed by infiltrating monocytes and resident Kupffer cells in livers from NASH-affected individuals. Using primary isolated human cells, we demonstrate that P2RX7 expression in CD14+ monocytes and Kupffer cells primarily mediates IL-1β release. In addition, we show that pharmacological inhibition of P2RX7 in monocytes and Kupffer cells, blocks IL-1β release, reducing hepatocyte caspase 3/7 activity, IL-1β-mediated CCL2 and CCL5 chemokine gene expression and secretion, and hepatic stellate cell (HSC) procollagen secretion. Consequently, in a chemically-induced nonhuman primate model of liver fibrosis, treatment with a P2RX7 inhibitor improved histological characteristics of NASH, protecting from liver inflammation and fibrosis. Taken together, these findings underscore the critical role of P2RX7 in the pathogenesis of NASH and implicate P2RX7 as a promising therapeutic target for the management of this disease.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1932-6203
Relation: https://doaj.org/toc/1932-6203
DOI: 10.1371/journal.pone.0234038
URL الوصول: https://doaj.org/article/fae6b5beb32246a08b1aa8288390bd23
رقم الأكسشن: edsdoj.fae6b5beb32246a08b1aa8288390bd23
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:19326203
DOI:10.1371/journal.pone.0234038