Role of necroptosis in the pathogenesis of solid organ injury

Abstract

Necroptosis is a type of regulated cell death dependent on the activity of receptor-interacting serine/threonine-protein (RIP) kinases. However, unlike apoptosis, it is caspase independent. Increasing evidence has implicated necroptosis in the pathogenesis of disease, including ischemic injury, neurodegeneration, viral infection and many others. Key players of the necroptosis signalling pathway are now widely recognized as therapeutic targets. Necrostatins may be developed as potent inhibitors of necroptosis, targeting the activity of RIPK1. Necrostatin-1, the first generation of necrostatins, has been shown to confer potent protective effects in different animal models. This review will summarize novel insights into the involvement of necroptosis in specific injury of different organs, and the therapeutic platform that it provides for treatment.

Figure 1

Signalling pathways after stimulation of the TNFR1. TNF-α is widely released during inflammatory conditions. (a) Upon binding to TNF receptor 1, TNF receptor 1 recruit TRADD, TRAF2 and 5, RIP-1, cIAPs and other molecules to form complex I. (b) Upon polyubiquitinated RIP-1, TNFR1-signalling activates NF-kB, leading to expression of proinflammatory cytokines. The deubiquitination of RIPK1 by CYLD leads to the formation of complex II. (c) Caspase-8 activation in complex II prevents necroptosis through preventing activation RIP, and suppresses the induction of necroptosis. (d) Inactivation of Caspase-8 in complex II leads to the phosphorylation and activation of RIPK1, RIPK3 and MLKL during the assembly of the necrosome. RIPK3 activates PGAM5 and Drp1 to induce reactive oxygen species (ROS) production in the mitochondria and mediate plasma membrane rupture. Abbreviation: TNF, tumor necrosis factor; TRADD, TNFRSF1A-associated via death domain; TRAF, TNF receptor associated factors; cIAPs, cellular inhibitor of apoptosis protein; CYLD, deubiquitinase cylindromatosis; MLKL, mediator mixed-lineage kinase domain like; RIP, receptor-interacting protein kinase; PGAM5, phosphoglycerate mutase 5; Drp1, dynamin-related protein 1

Figure 2

Necroptosis and inflammatory response. Necroptosis has been shown to commonly occur in the acute organ injury, especially in the organ transplantation. For example, during renal graft ischemia–reperfusion injury, (a) renal tubular epithelial cells undergoing necroptosis release DAMP molecules such as high-mobility group box 1 protein (HMGB-1), which is recognized by receptors, such as receptor for advanced glycation end products (RAGE) and Toll-like receptors 2, 4 and 9 (TLR-2, -4 and -9), reactive oxygen species (ROS) and inflammatory cytokines, such as TNF-α, leading to immune cell activation. (b) Inflammatory cells produce and release proinflammatory chemokine (e.g. CXCL1, CXCL2) and cytokines (e.g. IL-1 and -6) and promote tissue inflammation, infiltration of monocyte and neutrophils. (c) Infiltrating monocytes produce ROS and inflammatory cytokines such as TNF-α enhance the necroptosis in the epithelial cells. (d) Epithelial cells undergoing necroptosis could lead to the release and presentation of donor antigens by dendritic cells and activation of the acquired immune system, such as T cells and B cells. The immune rejection is then initiated. (e) Brown-Norway rat kidney was extracted and stored in UW solution for 24 h, and then transplanted into the Lewis recipient. Histology study demonstrated typical pathological progression possibly due to necroptosis. (1) Renal tubular cells. (2) Necrotic cells by ischemia–reperfusion injury 24 h after transplantation and (3) enhanced cellular infiltration during acute immune rejection 4 days after transplantation. The level of injury is gradually increased

Figure 3

Necroptosis and organ injury. Necroptosis has been identified in various organs, including heart, lung, liver, kidney, gastrointestinal tract and central nervous system