Programmed Necrosis in the Cross Talk of Cell Death and Inflammation

Abstract

Cell proliferation and cell death are integral elements in maintaining homeostatic balance in metazoans. Disease pathologies ensue when these processes are disturbed. A plethora of evidence indicates that malfunction of cell death can lead to inflammation, autoimmunity or immuno-deficiency. Programmed necrosis or necroptosis is a form of non-apoptotic cell death driven by the receptor interacting protein kinase 3 (RIPK3) and its substrate mixed lineage kinase domain-like (MLKL). RIPK3 partners with its upstream adaptors RIPK1, TRIF or DAI to signal for necroptosis in response to death receptor or toll-like receptor stimulation, pathogen infection, or sterile cell injury. Necroptosis promotes inflammation through leakage of cellular contents from damaged plasma membrane. Intriguingly, many of the signal adaptors of necroptosis have dual functions in innate immune signaling. This unique signature illustrates the cooperative nature of necroptosis and innate inflammatory signaling pathways in managing cell and organismal stresses from pathogen infection and sterile tissue injury.

Regulated RIPK3 Necroptosis is Produced in Cardiovascular Tissues and Cells in Dietary Magnesium Deficiency: Roles of Cytokines and Their Potential Importance in Inflammation and Atherogenesis

“…As a consequence, rupture of plasma membranes was evident from our studies, which ultimately results into significant losses of intracellular contents [67][68][69]. Moreover, similar experimentation in a rodent model system showed very similar characteristics in arterial and cardiac muscles, under high power TEM.…”

“…Employing transmission electron microscopy (TEM), in our Mg-deficient rabbit experimentation suggested to us that, both the vascular smooth muscle cells and macrophages of the lipid-laden arterial vessels exhibited necrosis and apoptosis [16,65,66, unpublished findings of Stempak, BT Altura, M Brust and BM Altura]. Further, investigation using TEM on cardiac and arterial muscle cells of Mg-deficient rats also showed clear signs of necrosis as well as apoptosis [66][67][68][69][70][71][72][73][74][75][76][77][78]; N Shah, BT Altura and BM Altura, unpublished findings]. Experimentation with high-power TEM revealed that, these Mg-deficient muscle cells exhibited what is now termed "necroptosis".…”

Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration

“…Necroptosis is a programmed form of necrosis, characterized by the rounding of the cell, gaining in cell volume, rupture of plasma membrane and release of intracellular contents [1,2]. Distinct from apoptosis, which is executed by proteases of the caspase family, necroptosis is thought to be a form of protease-independent cell death.…”

Regulation of RIPK3- and RHIM-dependent Necroptosis by the Proteasome

“…Caspase-dependent apoptosis is a key cell death module with important functions in development and certain disease pathologies. In addition to apoptosis, recent evidence shows that a form of regulated necrosis, termed necroptosis, is significantly associated with a number of common clinical diseases such as viral infection, ischemia-reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases (1,2). Necroptosis is driven by the cytosolic serine/threonine kinase receptor-interacting protein kinase 3 (RIPK3) 2 (3).…”

“…Necroptosis is driven by the cytosolic serine/threonine kinase receptor-interacting protein kinase 3 (RIPK3) 2 (3). A wide variety of stimuli including tumor necrosis factor (TNF) superfamily death ligands have been reported to induce necroptosis (1). Ligation of TNF to TNF receptor (TNFR) 1 causes formation of receptor-associated complex I, which comprises of TNFR1-associated via death domain (TRADD), TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis 1 (cIAP1), cIAP2, linear ubiquitin chain assembly complex (LUBAC), and RIPK1.…”