Many stimuli pull the necrotic trigger, an overview

Vanlangenakker, Nele; Berghe, Tom Vanden; Vandenabeele, Peter

doi:10.1038/cdd.2011.164

Cited by 363 publications

(343 citation statements)

References 168 publications

(313 reference statements)

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“…It has been shown that necroptosis is induced by ligand binding to TNF family death domain receptors, pattern recognition receptors, or virus sensors 53. Yet, our data suggest that neither TNFα nor other soluble factors are involved in sCD74/MIF‐induced necroptosis of cardiac myofibroblasts.…”

Section: Discussioncontrasting

confidence: 56%

“…The lack of proteolytic activity of caspase‐8 allows autophosphorylation of RIP1 and subsequent RIP3 and mixed lineage kinase domain‐like pseudokinase (MLKL) activation. Both phospho‐RIP3 and phospho‐MLKL assemble in so‐called necrosomes to trigger cell death 53. We assessed RIP3 activity by Western blot 10 hours after incubation with sCD74/rMIF and observed a 2‐fold increase of RIP3 phosphorylation compared with untreated control (control versus sCD74/rMIF: 100% versus 222.2±45.98%; P =0.0376, d =1.88), whereas neither rMIF nor sCD74 treatment alone affected phospho‐RIP3 levels (Figure 2C and 2D).…”

Section: Resultsmentioning

confidence: 99%

“…Myofibroblasts have been shown to produce and secrete TNFα,55 which mediates apoptosis‐ as well as necroptosis‐dependent cell death pathways 53. To test whether sCD74/rMIF‐triggered cell death is mediated by TNFα, we determined the mRNA level of TNFα after 8 hours as well as intra‐ and extracellular protein levels after 10 hours.…”

Section: Resultsmentioning

confidence: 99%

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Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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BackgroundAlthough macrophage migration inhibitory factor (MIF) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD74, the function of the soluble CD74 receptor ectodomain (sCD74) and its interaction with circulating MIF have not been explored in cardiac disease.Methods and ResultsCardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD74 induced cell death (P<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (RIP)1/RIP3‐dependent necroptosis (P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT‐qPCR technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with sCD74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD74 as a modulator of MIF signaling by diminishing MIF‐mediated protein kinase B (AKT) activation (P=0.0197) and triggering p38 activation (P=0.0641). We obtained evidence that sCD74 inhibits MIF‐mediated survival pathway through the C‐X‐C chemokine receptor 4/AKT axis, enabling the induction of CD74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD74/MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).ConclusionsThese findings suggest that treatment of cardiac myofibroblasts with sCD74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD74/MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

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Section: Discussioncontrasting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

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Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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“…This is surprising, because TNFinduced necroptosis is frequently considered to be more pro-inflammatory than TNF-initiated outcomes that occur in the presence of caspase activity. 22,[27][28][29] This view appears to be predicated upon the notion that TNF promotes either apoptosis or necrosis, with the latter typically being proinflammatory and the former not. However, because TNF is itself highly pro-inflammatory as illustrated above (Figures 1a and b), the impact of necroptosis on TNF-induced inflammatory events remains unclear.…”

Section: Resultsmentioning

confidence: 99%

Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production

et al. 2015

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“…RIPK1 is known to act in both caspase-dependent (apoptotic) and RIPK3-MLKL-dependent (necroptotic) death pathways. 32 To confirm which effectors were required downstream of RIPK1 for each death mechanism, we expressed RIPK1 gyrase in either WT MEFs or those lacking components of the death pathways. When RIPK1 gyrase was induced and dimerized in various lines of MEFs (Figure 3a), death occurred, except in the caspase 8 À / À line that also lacked RIPK3 (Figure 3b).…”

Section: Resultsmentioning

confidence: 99%

RIPK1- and RIPK3-induced cell death mode is determined by target availability

et al. 2014

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Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential for MLKL-dependent but not for caspase 8-dependent death. When RIPK1 or RIPK3 proteins were dimerized, the mode of cell death was determined by the availability of downstream molecules such as FADD, caspase 8 and MLKL. These observations imply that rather than a 'switch' operating between the two modes of cell death, the final mechanism depends on levels of the respective signaling and effector proteins. Mammalian cells can use a number of mechanisms to kill themselves. The best characterized depends on the Bcl-2 family members Bax and Bak that work via mitochondria to activate caspases. 1 Some caspases, notably caspase 8, can be activated independently of Bcl-2 family members, for example, after stimulation of members of the TNF receptor superfamily. 2 Recently, it has become apparent that some of these receptors, including TNFR1, can activate a third suicide mechanism that does not require caspases, and in which the morphology of the dying cell differs from classical apoptosis. This form of cell death, termed 'necroptosis', can often be blocked by necrostatin-1 (nec-1), an inhibitor of the kinase activity of receptor-interacting protein kinase 1 (RIPK1). 3,4 Accordingly, observations from several groups have shown that in some cell types, expression of RIPK1 can signal cell death by caspase-independent necroptosis. 5 It has previously been revealed that RIPK1 could function downstream of death receptors, but in those cases, cell death was usually blocked by coexpression of the viral inhibitor of caspases 1 and 8, CrmA, 6 and typically exhibited a classical 'apoptotic' morphology. It was revealed that RIPK1 engages FADD via homotypic binding of their death domains (DDs), and FADD in turn activates caspase 8. 6,7 RIPK3, like RIPK1, bears a kinase domain and RIP homology interaction motif (RHIM), but unlike RIPK1 does not have a DD. 8-11 RIPK3 is required for necroptosis. 12,13 Furthermore, RIPK1 appears to activate RIPK3 in this pathway, as cell death could be blocked by nec-1. 14 RIPK3 activates, by phosphorylation, MLKL, a pseudokinase essential for this death pathway. [15][16][17] Once activated, MLKL forms multimers that trigger breaches of the plasma membrane. [18][19][20] Although RIPK3 is necessary for necroptosis, it is unclear whether activation of RIPK3 is sufficient for cell death, because TNF activates signaling ...

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Many stimuli pull the necrotic trigger, an overview

Cited by 363 publications

References 168 publications

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production

RIPK1- and RIPK3-induced cell death mode is determined by target availability

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