Current translational potential and underlying molecular mechanisms of necroptosis

Abstract

Cell death has a fundamental impact on the evolution of degenerative disorders, autoimmune processes, inflammatory diseases, tumor formation and immune surveillance. Over the past couple of decades extensive studies have uncovered novel cell death pathways, which are independent of apoptosis. Among these is necroptosis, a tightly regulated, inflammatory form of cell death. Necroptosis contribute to the pathogenesis of many diseases and in this review, we will focus exclusively on necroptosis in humans. Necroptosis is considered a backup mechanism of apoptosis, but the in vivo appearance of necroptosis indicates that both caspase-mediated and caspase-independent mechanisms control necroptosis. Necroptosis is regulated on multiple levels, from the transcription, to the stability and posttranslational modifications of the necrosome components, to the availability of molecular interaction partners and the localization of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonineprotein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Accordingly, we classified the role of more than seventy molecules in necroptotic signaling based on consistent in vitro or in vivo evidence to understand the molecular background of necroptosis and to find opportunities where regulating the intensity and the modality of cell death could be exploited in clinical interventions. Necroptosis specific inhibitors are under development, but >20 drugs, already used in the treatment of various diseases, have the potential to regulate necroptosis. By listing necroptosis-modulated human diseases and cataloging the currently available drug-repertoire to modify necroptosis intensity, we hope to kick-start approaches with immediate translational potential. We also indicate where necroptosis regulating capacity should be considered in the current applications of these drugs. Facts • Necroptosis is closely associated with the pathogenesis of many human diseases. How effective can the off-label use of already approved drugs in necroptosis-driven diseases be?

Differences in the sensitivity of classically and alternatively activated macrophages to TAK1 inhibitor-induced necroptosis

“…More than 20 drugs, approved mostly in cancer therapy, but also in autoimmune or neurodegenerative disorders, have the potential to regulate necroptosis [18]. How these drugs modify the life span of M1/M2 cells still have not been investigated, but this effect may have influence on the current applications of necroptosis regulators.…”

“…Necroptosis is a regulated event rather than an accidental cell death process in which the most critical contributors are receptor-interacting protein 1 (RIPK1) [15], RIPK3 [16] and mixed lineage kinase domain like pseudokinase (MLKL) [17]. Necroptosis is known to play an important role in the pathogenesis of many diseases, such as neurodegenerative or inflammatory disorders, gastrointestinal, cardiovascular and pulmonary diseases [18]. The critical receptors of macrophages such as death, pattern recognition, DNA binding, cytokine and adhesion receptors all have been identified as potential inducers of necroptosis [19].…”

Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization — a Thomas Dougherty Award for Excellence in PDT paper

“…Necroptosis, another inflammatory type of programmed cell death with some similarities to pyroptosis, mimics features of apoptosis and necrosis, and is identified by membrane permeabilization and cell swelling [141][142][143]. Membrane pore formation during necroptosis disrupts the integrity of plasma membrane and causes cell death followed by the release of intracellular DAMPs.…”

Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

“…The mechanisms underlying the necroptosis pathway are mostly elucidated by a model of tumor necrosis factor alpha (TNFα)-induced cell death [ 8 , 9 , 35 , 36 , 37 , 38 ]. The binding of TNF to TNFR1 induces a conformational change in TNFR1 trimers, leading to the recruitment of a multiprotein platform named complex I, which includes RIPK1, TRADD (TNFR-associated death domain), cIAP1 (cellular inhibitor of apoptosis protein 1), cIAP2 and TRAF (TNFR-associated factor)2.…”

“…The receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3), as well as their target, the mixed lineage kinase domain-like protein (MLKL), are required to initiate necroptosis [ 5 , 6 , 7 ]. Necroptosis is associated with various human diseases including ischemic reperfusion injury, inflammatory, neurodegenerative, infectious, autoimmune diseases and cancer [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Recently, necroptosis has been also involved in mediating organ rejection in cardiac and renal allografts [ 8 , 12 , 19 , 20 , 21 , 22 ].…”