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We began analyzing https://www.nature.com/articles/cddis2013238, but it redirected us to https://www.nature.com/articles/cddis2013238. The analysis below is for the second page.

Title[redir]:
Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia | Cell Death & Disease
Description:
Microglia are the resident immune cells in the central nervous system and key players against pathogens and injury. However, persistent microglial activation often exacerbates pathological damage and has been implicated in many neurological diseases. Despite their pivotal physiological and pathophysiological roles, how the survival and death of activated microglia is regulated remains poorly understood. We report here that microglia activated through Toll-like receptors (TLRs) undergo RIP1/RIP3-dependent programmed necrosis (necroptosis) when exposed to the pan caspase inhibitor zVAD-fmk. Although zVAD-fmk and the caspase-8 inhibitor IETD-fmk had no effect on unstimulated primary microglia, they markedly sensitized microglia to TLR1/2,3,4,7/8 ligands or TNF treatment, triggering programmed necrosis that was completely blocked by R1P1 kinase inhibitor necrostatin-1. Interestingly, necroptosis induced by TLR ligands and zVAD was restricted to microglial cells and was not observed in astrocytes, neurons or oligodendrocytes even though they are known to express certain TLRs. Deletion of genes encoding TNF or TNFR1 failed to prevent lipopolysaccharide- and poly(I:C)-induced microglial necroptosis, unveiling a TNF-independent programmed necrosis pathway in TLR3- and TLR4-activated microglia. Microglia from mice lacking functional TRIF were fully protected against TLR3/4 activation and zVAD-fmk-induced necrosis, and genetic deletion of rip3 also prevented microglia necroptosis. Activation of c-jun N-terminal kinase and generation of specific reactive oxygen species were downstream signaling events required for microglial cell death execution. Taken together, this study reveals a robust RIP3-dependent necroptosis signaling pathway in TLR-activated microglia upon caspase blockade and suggests that TLR signaling and programmed cell death pathways are closely linked in microglia, which could contribute to neuropathology and neuroinflammation when dysregulated.

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  • Science
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🌠 Phenomenal Traffic: 5M - 10M visitors per month


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Keywords {πŸ”}

microglia, cell, death, caspase, article, necrosis, microglial, rip, lps, google, scholar, activation, cas, tlr, cells, figure, necroptosis, tnf, activated, data, programmed, primary, treated, trif, production, usa, inhibitor, ngml, lpszvad, zvadfmk, kinase, cns, apoptosis, nec, independent, cultures, lpszvadinduced, nature, tolllike, survival, determined, receptor, jnk, mixed, immune, zvad, rat, experiments, oligodendrocytes, signaling,

Topics {βœ’οΈ}

nature portfolio research grants ns060017 nature reviews neurology privacy policy c-jun n-terminal kinase receptor-interacting kinase-3-mediated pathway advertising fluorescein-tagged fam-letd-fmk nature 2011 nature tlr/zvad-induced necroptosis pathway poly-l-ornithine-coated culture plates social media arachidonic acid-induced necroptosis lps/zvad-induced microglial necrosis prevent lps/zvad-induced necrosis author information authors lps/zvad-induced cell death lps/zvad-induced microglial necroptosis 0/ reprints early embryonic development 50 μg/ml human apo-transferrin death receptor-induced pathway china japan /zvad-induced programmed necrosis rip3-mediated programmed necrosis cross-journal web focus /zvad-induced microglial necrosis lipopolysaccharide-induced cell death host-derived molecules liberated bone marrow-derived monocytes activation-induced cell death tlr4-induced microglial necroptosis tlr-activation-induced necroptosis lipopolysaccharide-induced oligodendrocyte injury wild-type control c57bl/6j zvad-fmk-induced necrosis alternative necrosis-initiating pathways author correspondence lps/zvad-induced necrosis fluorescent fam-letd-fmk receptor-mediated neuronal injury small tryptophan-based molecule lps/zvad-induced necroptosis rip3 mediated lps/zvad lps/zvad-induced increased hrp-conjugated secondary antibodies tlr ligands/zvad occurs caspase-3/7 inhibitor devd-fmk

Questions {❓}

  • What does the commonly used DCF test for oxidative stress really show?

Schema {πŸ—ΊοΈ}

WebPage:
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         headline:Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia
         description:Microglia are the resident immune cells in the central nervous system and key players against pathogens and injury. However, persistent microglial activation often exacerbates pathological damage and has been implicated in many neurological diseases. Despite their pivotal physiological and pathophysiological roles, how the survival and death of activated microglia is regulated remains poorly understood. We report here that microglia activated through Toll-like receptors (TLRs) undergo RIP1/RIP3-dependent programmed necrosis (necroptosis) when exposed to the pan caspase inhibitor zVAD-fmk. Although zVAD-fmk and the caspase-8 inhibitor IETD-fmk had no effect on unstimulated primary microglia, they markedly sensitized microglia to TLR1/2,3,4,7/8 ligands or TNF treatment, triggering programmed necrosis that was completely blocked by R1P1 kinase inhibitor necrostatin-1. Interestingly, necroptosis induced by TLR ligands and zVAD was restricted to microglial cells and was not observed in astrocytes, neurons or oligodendrocytes even though they are known to express certain TLRs. Deletion of genes encoding TNF or TNFR1 failed to prevent lipopolysaccharide- and poly(I:C)-induced microglial necroptosis, unveiling a TNF-independent programmed necrosis pathway in TLR3- and TLR4-activated microglia. Microglia from mice lacking functional TRIF were fully protected against TLR3/4 activation and zVAD-fmk-induced necrosis, and genetic deletion of rip3 also prevented microglia necroptosis. Activation of c-jun N-terminal kinase and generation of specific reactive oxygen species were downstream signaling events required for microglial cell death execution. Taken together, this study reveals a robust RIP3-dependent necroptosis signaling pathway in TLR-activated microglia upon caspase blockade and suggests that TLR signaling and programmed cell death pathways are closely linked in microglia, which could contribute to neuropathology and neuroinflammation when dysregulated.
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      headline:Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia
      description:Microglia are the resident immune cells in the central nervous system and key players against pathogens and injury. However, persistent microglial activation often exacerbates pathological damage and has been implicated in many neurological diseases. Despite their pivotal physiological and pathophysiological roles, how the survival and death of activated microglia is regulated remains poorly understood. We report here that microglia activated through Toll-like receptors (TLRs) undergo RIP1/RIP3-dependent programmed necrosis (necroptosis) when exposed to the pan caspase inhibitor zVAD-fmk. Although zVAD-fmk and the caspase-8 inhibitor IETD-fmk had no effect on unstimulated primary microglia, they markedly sensitized microglia to TLR1/2,3,4,7/8 ligands or TNF treatment, triggering programmed necrosis that was completely blocked by R1P1 kinase inhibitor necrostatin-1. Interestingly, necroptosis induced by TLR ligands and zVAD was restricted to microglial cells and was not observed in astrocytes, neurons or oligodendrocytes even though they are known to express certain TLRs. Deletion of genes encoding TNF or TNFR1 failed to prevent lipopolysaccharide- and poly(I:C)-induced microglial necroptosis, unveiling a TNF-independent programmed necrosis pathway in TLR3- and TLR4-activated microglia. Microglia from mice lacking functional TRIF were fully protected against TLR3/4 activation and zVAD-fmk-induced necrosis, and genetic deletion of rip3 also prevented microglia necroptosis. Activation of c-jun N-terminal kinase and generation of specific reactive oxygen species were downstream signaling events required for microglial cell death execution. Taken together, this study reveals a robust RIP3-dependent necroptosis signaling pathway in TLR-activated microglia upon caspase blockade and suggests that TLR signaling and programmed cell death pathways are closely linked in microglia, which could contribute to neuropathology and neuroinflammation when dysregulated.
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