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Necroptosis in Intestinal Inflammation and Cancer

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Necroptosis in Intestinal Inflammation and Cancer biomolecules Review Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives Anna Negroni 1,* , Eleonora Colantoni 2, Salvatore Cucchiara 2 and Laura Stronati 3 1 Division of Health Protection Technologies, ENEA, 00123 Rome, Italy 2 Maternal Infantile and Urological Sciences Department, Sapienza, University of Rome, 00161 Rome, Italy; [email protected] (E.C.); [email protected] (S.C.) 3 Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-06-3048-3623 Received: 3 September 2020; Accepted: 8 October 2020; Published: 10 October 2020 Abstract: Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery. Keywords: programmed cell death; inflammation; cancer; intestinal diseases; inhibitors 1. Introduction Cell death is crucial during the development and maintenance of tissue homeostasis in multicellular organisms. Until recently, apoptosis was considered the only molecularly controlled type of cell death, as opposed to necrosis, which was classically described as nonregulated accidental cell death. Several types of programmed necrotic cell death have been recently identified, which, although sharing common morphological features, such as cellular volume increase, organelles swelling, and plasma membrane disruption, however, respond to different triggers and follow distinct biochemical pathways [1]. Necroptosis is a programmed necrosis executed by the activation of death receptors including tumor necrosis factor receptor 1 (TNFR1), Fas receptor (FasR), TNF-related apoptosis-inducing ligand–death receptor 1 (TRAILR1), interferon receptor (IFNR) and also pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-like receptors (RLRs) [2–4]. 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 [5–7]. Necroptosis is associated with various human diseases including ischemic reperfusion injury, inflammatory, neurodegenerative, infectious, autoimmune diseases and cancer [8–18]. Recently, necroptosis has been also involved in mediating organ rejection in cardiac and renal allografts [8,12,19–22]. Despite the pathological connotation that characterized necroptosis at the beginning of its identification, emerging evidence points to its crucial role in physiological phenomena such as development, immunology and differentiation. For example, mutant mice with kinase-dead RIPK1 Biomolecules 2020, 10, 1431; doi:10.3390/biom10101431 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, x 2 of 20 Biomolecules 2020, 10, 1431 2 of 20 Despite the pathological connotation that characterized necroptosis at the beginning of its identification, emerging evidence points to its crucial role in physiological phenomena such as or RIPK3development, and MLKL immunology deficiency and show differentiation. no detrimental For example, phenotype mutant with mice regard with kinase-dead to development RIPK1 and adultor homeostasis RIPK3 and MLKL [10]. deficiency Furthermore, show no several detrimental authors phenotype report thatwith regard necroptosis to development is able to and induce the innateadult homeostasis immune response [10]. Furthermore, to viral infections, several authors when report the virus that necroptosis inhibits host is able apoptotic to induce machinery the and cellsinnate are immune committed response to alternativeto viral infections, cell death when tothe limit virus viral inhibits replication host apoptotic or generate machinery an immuneand cells are committed to alternative cell death to limit viral replication or generate an immune response response [23–27]. Necroptosis is also implicated in the regulation of antigen-activated T-cell proliferation [23–27]. Necroptosis is also implicated in the regulation of antigen-activated T-cell proliferation and and survival [28,29]. survival [28,29]. In thisIn review,this review, the the molecular molecular mechanisms mechanisms of of necroptosis necroptosis asas well as as its its role role in in the the pathogenesis pathogenesis of gastrointestinalof gastrointestinal (GI) tract (GI) diseasestract diseases and and necroptosis-targeted necroptosis-targeted therapies therapies willwill bebe discussed. 2. Necroptosis2. Necroptosis Signaling Signaling Pathway Pathway NecroptosisNecroptosis is ais cellulara cellular responseresponse to to environmen environmentaltal stress stress that can that be can caused be causedby chemical by chemicaland and mechanical injury, injury, inflammation, inflammation, or infection. or infection. In addition In addition to traditional to traditional triggers (Figure triggers 1), recent (Figure 1), recentevidence evidence shows shows that that necroptosis necroptosis can be can also be induced also induced by DNA by damage, DNA damage, environmental environmental stresses, such stresses, suchas as the the hypoxia hypoxia and and glucose glucose level, level, and andchemotherapeutic chemotherapeutic agents agents [30–34]. [ 30 –34]. FigureFigure 1. Necroptosis 1. Necroptosis signaling signaling triggers. triggers. TLR, Toll-like Toll-like receptor; receptor; LPS, LPS, lipopolysaccharide; lipopolysaccharide; TNFα TNF, α, tumortumor necrosis necrosis factor factor alpha; alpha; TNFR1, TNFR1, tumor tumor necrosisnecrosis factor factor receptor; receptor; FasL, FasL, Fas Fas ligand; ligand; IFN, IFN, interferon; interferon; IFNR,IFNR, interferon interferon receptor; receptor; TRIF, TRIF, Toll Toll/interleukin/interleukin-1-1 receptor (TIR) (TIR) domain-containing domain-containing interferon- interferon-β; β; DAI,DAI, DNA-dependent DNA-dependent activator activator of of IFN IFN regulatory regulatory factors; RHIM, RHIM, RIP-homotypic-interaction-motif RIP-homotypic-interaction-motif domain;domain; RIPK3, RIPK3, receptor-interacting receptor-interacting protein protein kinase kinase 3. The mechanismsThe mechanisms underlying underlying the the necroptosis necroptosis pathwaypathway are are mostly mostly elucidated elucidated by a by model a model of tumor of tumor necrosis factor alpha (TNFα)-induced cell death [8,9,35–38]. The binding of TNF to TNFR1 induces a necrosis factor alpha (TNFα)-induced cell death [8,9,35–38]. The binding of TNF to TNFR1 induces conformational change in TNFR1 trimers, leading to the recruitment of a multiprotein platform 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 namedinhibitor complex of apoptosis I, which protein includes 1), cIAP2 RIPK1, and TRADD TRAF (TNFR-associated (TNFR-associated factor)2. death The domain), polyubiquitination cIAP1 (cellular inhibitorof RIPK1 of apoptosis by cIAP1/2 protein causes 1), the cIAP2 recruitment and TRAF of complexes (TNFR-associated IKK (IKKα, factor)2.IKKβ and The NEMO) polyubiquitination and TAK1 of RIPK1(TAK1, by TAB1 cIAP1 and/2 causesTAB2), leading the recruitment to the activation of complexes of the transcription IKK (IKK factorα, IKK NF-kBβ and and NEMO) cell survival. and TAK1 (TAK1,The TAB1 deubiquitination and TAB2), of leading RIPK1 toby the deubiquitinase activation of cylindromatosis the transcription (CYLD) factor or NF-kB the A20 and ubiquitin- cell survival. The deubiquitinationediting complex marks of RIPK1 the transition by deubiquitinase from complex cylindromatosis I to complex II and (CYLD) inhibits or theNF- A20κB activation ubiquitin-editing [39]. complexTRADD marks and theRIPK1 transition dissociate from from complexTNFR1 recruiting I to complex Fad- associated II and inhibits protein with NF-κ deathB activation domain [39]. TRADD(FADD) and and RIPK1 pro-caspase-8 dissociate and from leading TNFR1 to the recruitingformation of Fad- complex associated IIa, which protein results within the deathactivation domain of caspase-8 cleavage followed by apoptosis [40]. (FADD) and pro-caspase-8 and leading to the formation of complex IIa, which results in the activation of caspase-8 cleavage followed by apoptosis [40]. The enrollment of RIPK3 causes the formation of complex IIb. Recent scientific advances have revealed the role of the cellular FLICE-inhibitory protein (cFLIP) as a critical switch to control cell survival and death in various tissues. cFLIP protein is evolutionarily conserved and expressed as Biomolecules 2020, 10, 1431 3 of 20 Biomolecules 2020,
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