Necrosome Formation and Necroptosis in Experimental Cholestasis
Necroptosis is emerging as a critical pathogenic mechanism in several liver diseases, including cholestatic disorders. Necroptosis was recently described as a novel cell death subroutine, activated downstream of death receptor stimulation and dependent on
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ction Cholestatic liver diseases comprise an array of human disorders and syndromes that may arise from several inflicting insults, including genetic defects, toxin or drug toxicity, dysregulation of the immune system, hepatobiliary malignancies, or obstruction of the biliary tract [1]. Despite its heterogeneity, cholestasis shares basic hepatocyte and cholangiocyte-targeting processes that contribute to disease pathogenesis, namely pro-inflammatory signaling, innate immune response, liver cell death, cholangiocyte proliferation, as well as tissue repair processes [2]. The pathways governing cell demise and inflammation are still not fully understood; however, necroptosis is emerging as a relevant immunogenic cell death subroutine implicated in the pathogenesis of cholestasis [3–5]. In fact, biological markers of necroptosis have been found in cells morphologically resembling bile duct epithelia and in hepatocytes surrounded by inflammatory cells in primary biliary cholangitis (PBC) Mathieu Vinken (ed.), Experimental Cholestasis Research, Methods in Molecular Biology, vol. 1981, https://doi.org/10.1007/978-1-4939-9420-5_10, © Springer Science+Business Media, LLC, part of Springer Nature 2019
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Marta B. Afonso and Cecília M. P. Rodrigues
patients. Further, it has been shown that necroptosis is triggered in the liver of mice subjected to common bile duct ligation, mediating necro-inflammation at both acute and chronic phases [3, 4]. Nevertheless, the role of necroptosis in the pathogenesis of a broad range of cholestatic liver diseases remains to be elucidated. The term “necroptosis” was firstly used to describe a regulated form of necrosis depending on the kinase activity of receptor- interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 in 2005, with the discovery of necrostatin-1 as a potent inhibitor of RIPK1 kinase activity [6]. Necroptosis is now defined as a variant of regulated necrosis that critically depends on RIPK3 kinase activity and mixed lineage kinase domain-like (MLKL) [7]. Briefly, necroptosis is initiated by death receptors such as tumor necrosis factor-α (TNF-α). After ligand binding, when caspases are inhibited or RIPK3 protein levels are increased, RIPK1 and RIPK3 engage in physical interactions originating an oligomeric amyloid signaling complex named necrosome. In turn, RIPK3 recruits and phosphorylates MLKL, which also oligomerizes leading to cell permeabilization with concomitant tissue damage and inflammation [8] (Fig. 1). Necroptosis and apoptosis are regulated by overlapping molecular machineries and are capable of acting as a backup of each other when one of them fails. Mounting evidence suggests that, rather than a “switch” operating between apoptosis and necroptosis in response to TNF-α signaling, it is the relative levels and activity of RIPK1, RIPK3, caspase-8, and MLKL that will ultimately dictate the outcome of the cell death mechanism [9–11]. Adding to this complexity, multiple lines of evidence support that core components of the necroptotic machinery actively
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