Abstract
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.
Highlights
Hepatocyte injury, inflammation, and immune cell activation are common features of the pathogenesis of most liver diseases, including non-alcoholic steatohepatitis (NASH) [1]
Levels of mature IL-1β (Fig 1C), caspase-1 (Fig 1D), NOD-like receptor family pyrin domain containing 3 (NLRP3), IL-1β, CASP1, and AIM2 mRNA (Fig 1G) and CCL2 and CCL5 chemokines (Fig 1E and 1F), key mediators of inflammatory cell recruitment, were significantly elevated in NASHaffected liver biopsies compared to healthy controls, confirming earlier studies [14,15,35,36]
These results suggest that the higher abundance of P2RX7+ cells in NASH-affected livers is associated with increased numbers of resident and infiltrating macrophages and increased inflammation and fibrosis
Summary
Hepatocyte injury, inflammation, and immune cell activation are common features of the pathogenesis of most liver diseases, including non-alcoholic steatohepatitis (NASH) [1]. Persistent and progressive hepatic inflammation has been associated with the development of liver fibrosis [2,3], which can lead to cirrhosis, hepatocellular carcinoma, and liver failure [4]. As such, controlling the early onset of hepatic inflammation might preclude the development. National Institutes of Health R01 DK101737, U01 AA022614, R01 DK099205, P50AA011999 to T.K. and D.A.B
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