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Revisiting caspases in sepsis.

Aziz M, Jacob A, Wang P - Cell Death Dis (2014)

Bottom Line: Recently, interest has been shifted toward therapies aimed at reversing the accompanying periods of immune suppression.Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy and organ dysfunction.In addition, we have documented striking perspectives which not only rewrite the pathophysiology, but also modernize our understanding for developing novel therapeutics against sepsis.

View Article: PubMed Central - PubMed

Affiliation: 1] Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA.

ABSTRACT
Sepsis is a life-threatening illness that occurs due to an abnormal host immune network which extends through the initial widespread and overwhelming inflammation, and culminates at the late stage of immunosupression. Recently, interest has been shifted toward therapies aimed at reversing the accompanying periods of immune suppression. Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy and organ dysfunction. Immediate to the discoveries of the intracellular proteases, caspases for the induction of apoptosis and inflammation, and their striking roles in sepsis have been focused elaborately in a number of original and review articles. Here we revisited the different aspects of caspases in terms of apoptosis, pyroptosis, necroptosis and inflammation and focused their links in sepsis by reviewing several recent findings. In addition, we have documented striking perspectives which not only rewrite the pathophysiology, but also modernize our understanding for developing novel therapeutics against sepsis.

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Related in: MedlinePlus

RIP1/3-mediated necroptosis: tumor necrosis factor (TNF) binding to itstrimeric receptor, TNF receptor-1 (TNFR1) leads to a conformational change togenerate TNFR complex I, which includes TNF receptor-associated death domain(TRADD), receptor-interacting protein 1 (RIP1; also known as RIPK1), cellularinhibitor of apoptosis proteins (cIAPs), TNF receptor-associated factor 2 (TRAF2)and TRAF5. Upon TNFR1 activation, linear ubiquitin chain assembly complex (LUBAC)promotes the recruitment and ubiquitination of the IKK-complex component, nuclearfactor-κB (NF-κB) essential modulator (NEMO, alsoknown as IKKγ). Ubiquitination of NEMO by LUBAC leads toNF-κB phosphorylation, activation and translocation into thenucleus for inducing pro-inflammatory gene expression. A20 acts as a negativeregulator of NF-κB activation. In parallel, LUBAC also assures thelinear polyubiquitinylation of RIP1, therefore preventing the exposition of theRIP1-assembly region that is required for complex II formation. Similarly, cIAPsis also involved in the polyubiquitinylation of RIP1. If RIP1 is deubiquitinylatedby LUBAC inactivation, RIP1 will bind to RIP3 and activate the downstream cascadeof necroptosis. Normally, caspase-8 triggers apoptosis by activating the classicalcaspase cascade. It also cleaves, and hence inactivates, RIP1 and RIP3. Ifcaspase-8 is blocked by pharmacological or genetic interventions, RIP1 and RIP3become phosphorylated by an unidentified kinase and engage the effector mechanismsof necroptosis. Necrostatin-1 (Nec-1) has been named for its ability to blocknecroptosis. Nec-1 is an allosteric inhibitor of RIP1 kinase activity
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fig3: RIP1/3-mediated necroptosis: tumor necrosis factor (TNF) binding to itstrimeric receptor, TNF receptor-1 (TNFR1) leads to a conformational change togenerate TNFR complex I, which includes TNF receptor-associated death domain(TRADD), receptor-interacting protein 1 (RIP1; also known as RIPK1), cellularinhibitor of apoptosis proteins (cIAPs), TNF receptor-associated factor 2 (TRAF2)and TRAF5. Upon TNFR1 activation, linear ubiquitin chain assembly complex (LUBAC)promotes the recruitment and ubiquitination of the IKK-complex component, nuclearfactor-κB (NF-κB) essential modulator (NEMO, alsoknown as IKKγ). Ubiquitination of NEMO by LUBAC leads toNF-κB phosphorylation, activation and translocation into thenucleus for inducing pro-inflammatory gene expression. A20 acts as a negativeregulator of NF-κB activation. In parallel, LUBAC also assures thelinear polyubiquitinylation of RIP1, therefore preventing the exposition of theRIP1-assembly region that is required for complex II formation. Similarly, cIAPsis also involved in the polyubiquitinylation of RIP1. If RIP1 is deubiquitinylatedby LUBAC inactivation, RIP1 will bind to RIP3 and activate the downstream cascadeof necroptosis. Normally, caspase-8 triggers apoptosis by activating the classicalcaspase cascade. It also cleaves, and hence inactivates, RIP1 and RIP3. Ifcaspase-8 is blocked by pharmacological or genetic interventions, RIP1 and RIP3become phosphorylated by an unidentified kinase and engage the effector mechanismsof necroptosis. Necrostatin-1 (Nec-1) has been named for its ability to blocknecroptosis. Nec-1 is an allosteric inhibitor of RIP1 kinase activity

Mentions: Different cellular stimuli (e.g., TNF, FAS ligand, TRAIL ligand, double-strandedRNA, interferon-γ (IFN-γ), ATP and pathogens) havebeen shown to induce necrosis that follows defined signaling events reminiscent ofa cell-death program15 (Figure 3). Necroptosis can be defined as cell deathmediated through a pathway that depends on the receptor-interacting protein kinase1 (RIPK1 or RIP1)–RIPK3 complex and that can be inhibited by Necrostatin-1(Nec-1).16 RIPK3 or RIP3 can alsoform complexes with DNA-dependent activator of IFN regulatory factor and theadaptor molecule TIR domain-containing adaptor-inducing IFN-β,leading to RIPK3-dependent programmed necrosis.16, 17


Revisiting caspases in sepsis.

Aziz M, Jacob A, Wang P - Cell Death Dis (2014)

RIP1/3-mediated necroptosis: tumor necrosis factor (TNF) binding to itstrimeric receptor, TNF receptor-1 (TNFR1) leads to a conformational change togenerate TNFR complex I, which includes TNF receptor-associated death domain(TRADD), receptor-interacting protein 1 (RIP1; also known as RIPK1), cellularinhibitor of apoptosis proteins (cIAPs), TNF receptor-associated factor 2 (TRAF2)and TRAF5. Upon TNFR1 activation, linear ubiquitin chain assembly complex (LUBAC)promotes the recruitment and ubiquitination of the IKK-complex component, nuclearfactor-κB (NF-κB) essential modulator (NEMO, alsoknown as IKKγ). Ubiquitination of NEMO by LUBAC leads toNF-κB phosphorylation, activation and translocation into thenucleus for inducing pro-inflammatory gene expression. A20 acts as a negativeregulator of NF-κB activation. In parallel, LUBAC also assures thelinear polyubiquitinylation of RIP1, therefore preventing the exposition of theRIP1-assembly region that is required for complex II formation. Similarly, cIAPsis also involved in the polyubiquitinylation of RIP1. If RIP1 is deubiquitinylatedby LUBAC inactivation, RIP1 will bind to RIP3 and activate the downstream cascadeof necroptosis. Normally, caspase-8 triggers apoptosis by activating the classicalcaspase cascade. It also cleaves, and hence inactivates, RIP1 and RIP3. Ifcaspase-8 is blocked by pharmacological or genetic interventions, RIP1 and RIP3become phosphorylated by an unidentified kinase and engage the effector mechanismsof necroptosis. Necrostatin-1 (Nec-1) has been named for its ability to blocknecroptosis. Nec-1 is an allosteric inhibitor of RIP1 kinase activity
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4260746&req=5

fig3: RIP1/3-mediated necroptosis: tumor necrosis factor (TNF) binding to itstrimeric receptor, TNF receptor-1 (TNFR1) leads to a conformational change togenerate TNFR complex I, which includes TNF receptor-associated death domain(TRADD), receptor-interacting protein 1 (RIP1; also known as RIPK1), cellularinhibitor of apoptosis proteins (cIAPs), TNF receptor-associated factor 2 (TRAF2)and TRAF5. Upon TNFR1 activation, linear ubiquitin chain assembly complex (LUBAC)promotes the recruitment and ubiquitination of the IKK-complex component, nuclearfactor-κB (NF-κB) essential modulator (NEMO, alsoknown as IKKγ). Ubiquitination of NEMO by LUBAC leads toNF-κB phosphorylation, activation and translocation into thenucleus for inducing pro-inflammatory gene expression. A20 acts as a negativeregulator of NF-κB activation. In parallel, LUBAC also assures thelinear polyubiquitinylation of RIP1, therefore preventing the exposition of theRIP1-assembly region that is required for complex II formation. Similarly, cIAPsis also involved in the polyubiquitinylation of RIP1. If RIP1 is deubiquitinylatedby LUBAC inactivation, RIP1 will bind to RIP3 and activate the downstream cascadeof necroptosis. Normally, caspase-8 triggers apoptosis by activating the classicalcaspase cascade. It also cleaves, and hence inactivates, RIP1 and RIP3. Ifcaspase-8 is blocked by pharmacological or genetic interventions, RIP1 and RIP3become phosphorylated by an unidentified kinase and engage the effector mechanismsof necroptosis. Necrostatin-1 (Nec-1) has been named for its ability to blocknecroptosis. Nec-1 is an allosteric inhibitor of RIP1 kinase activity
Mentions: Different cellular stimuli (e.g., TNF, FAS ligand, TRAIL ligand, double-strandedRNA, interferon-γ (IFN-γ), ATP and pathogens) havebeen shown to induce necrosis that follows defined signaling events reminiscent ofa cell-death program15 (Figure 3). Necroptosis can be defined as cell deathmediated through a pathway that depends on the receptor-interacting protein kinase1 (RIPK1 or RIP1)–RIPK3 complex and that can be inhibited by Necrostatin-1(Nec-1).16 RIPK3 or RIP3 can alsoform complexes with DNA-dependent activator of IFN regulatory factor and theadaptor molecule TIR domain-containing adaptor-inducing IFN-β,leading to RIPK3-dependent programmed necrosis.16, 17

Bottom Line: Recently, interest has been shifted toward therapies aimed at reversing the accompanying periods of immune suppression.Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy and organ dysfunction.In addition, we have documented striking perspectives which not only rewrite the pathophysiology, but also modernize our understanding for developing novel therapeutics against sepsis.

View Article: PubMed Central - PubMed

Affiliation: 1] Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA.

ABSTRACT
Sepsis is a life-threatening illness that occurs due to an abnormal host immune network which extends through the initial widespread and overwhelming inflammation, and culminates at the late stage of immunosupression. Recently, interest has been shifted toward therapies aimed at reversing the accompanying periods of immune suppression. Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy and organ dysfunction. Immediate to the discoveries of the intracellular proteases, caspases for the induction of apoptosis and inflammation, and their striking roles in sepsis have been focused elaborately in a number of original and review articles. Here we revisited the different aspects of caspases in terms of apoptosis, pyroptosis, necroptosis and inflammation and focused their links in sepsis by reviewing several recent findings. In addition, we have documented striking perspectives which not only rewrite the pathophysiology, but also modernize our understanding for developing novel therapeutics against sepsis.

Show MeSH
Related in: MedlinePlus