A Role for Granzyme M in TLR4-Driven Inflammation and Endotoxicosis

Human and mouse granzyme (Gzm)B both induce target cell apoptosis in concert with pore-forming perforin (Pfp); however the mechanisms by which other Gzms induce non-apoptotic death remain controversial and poorly characterised. We used timelapse microscopy to document, quantitatively and in real time, the death of target cells exposed to primary natural killer (NK) cells from mice deficient in key Gzms. We found that in the vast majority of cases, NK cells from wild-type mice induced classic apoptosis. However, NK cells from syngeneic Gzm B-deficient mice induced a novel form of cell death characterised by slower kinetics and a pronounced, writhing, 'worm-like' morphology. Dying cells initially contracted but did not undergo membrane blebbing, and annexin-V staining was delayed until the onset of secondary necrosis. As it is different from any cell death process previously reported, we tentatively termed this cell death 'athetosis'. Two independent lines of evidence showed this alternate form of death was due to Gzm A: first, cell death was revealed in the absence of Gzm B, but was completely lost when the NK cells were deficient in both Gzm A and B; second, the athetotic morphology was precisely reproduced when recombinant mouse Gzm A was delivered by an otherwise innocuous dose of recombinant Pfp. Gzm A-mediated athetosis did not require caspase activation, early mitochondrial disruption or generation of reactive oxygen species, but did require an intact actin cytoskeleton and was abolished by latrunculin B and mycalolide B. This work defines an authentic role for mouse Gzm A in granule-induced cell death by cytotoxic lymphocytes.

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“…[8][9][10]24 Here, we have demonstrated that cell death can be induced when mGzmA is delivered by NKs via authentic CL/target cell interactions.…”

Section: Discussionmentioning

confidence: 83%

Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis

et al. 2013

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“…10 The physiological importance of this phenomenon was then validated by showing that gzmA knockout (ko) mice (gzmA À/À ) resist the lethal effects of LPS. 8 Together with the recent finding that (Mo)gzmM augments TLR4-driven inflammation and endotoxicosis, 11 these observations set a biological precedent indicating that (Hu/Mo)gzms may have additional functions besides acting as pro-apoptotic mediators.…”

mentioning

confidence: 75%

Mouse granzyme K has pro-inflammatory potential

et al. 2011

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Granzymes (gzms) are key components of T-killer (Tc) cells believed to mediate pro-apoptotic activities. Recent evidence suggests that gzms also possess non-cytotoxic activities that contribute to host defense. In this study, we show that Tc cells from lymphocytic choriomeningitis virus (LCMV)-infected wild-type (wt) and gzm A/B-deficient mice express similar levels of gzmK protein, with both mouse strains efficiently controlling infection. GzmK, in recombinant form or secreted by ex vivoderived LCMV-immune gzmAxB À/À Tc cells, lacks pro-apoptotic activity. Instead, gzmK induces primary mouse macrophages to process and secrete interleukin-1b, independent of the ATP receptor P2X 7 . Together with the finding that IL-1Ra (Anakinra) treatment inhibits virus elimination but not generation of cytotoxic Tc cells in wt mice, the data suggest that Tc cells control LCMV through non-cytotoxic processes that involve gzmK.

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“…This cleavage is indicated by scissors. We have reported Gr functions independent of their catalytic activity (48 and GrAB 2/2 mice were not directly compared in their experiments (44). The interplay between GrA and GrB in the immune response to LPS is unresolved and deserves further study.…”

Section: Grs Trigger Cytokine Release and Activationmentioning

confidence: 92%

“…Studies in mice show a role for GrA in the inflammatory response to the Gram-negative bacterial cell wall component LPS. GrA 2/2 mice better withstand a lethal LPS challenge in that they survive longer than do wild-type (WT) mice (11,44). Furthermore, hGrA exerts direct effects on several cell types to induce cytokine release in vitro.…”

Section: Grs Trigger Cytokine Release and Activationmentioning

confidence: 99%

“…Data on GrB knockout mice survival upon LPS challenge are conflicting. Anthony et al (44) show that deletion of GrB has no effect on survival upon LPS challenge, whereas Metkar et al (11) showed that GrB knockout results in a marked increase in survival that exceeds the effect of GrA deletion. Thus, the effect of GrB on the immune response to LPS remains to be elucidated.…”

Section: Grs Trigger Cytokine Release and Activationmentioning

confidence: 99%

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Granzymes Regulate Proinflammatory Cytokine Responses

Wensink

Hack

Bovenschen

2015

The Journal of Immunology

120

153

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Granzymes (Grs) are serine proteases mainly produced by cytotoxic lymphocytes and are traditionally considered to cause apoptosis in tumor cells and virally infected cells. However, the cytotoxicity of several Grs is currently being debated, and additional, predominantly extracellular, functions of Grs in inflammation are emerging. Extracellular soluble Grs are elevated in the circulation of patients with autoimmune diseases and infections. Additionally, Grs are expressed by several types of immune cells other than cytotoxic lymphocytes. Recent research has revealed novel immunomodulatory functions of Grs. In this review, we provide a comprehensive overview on the role of Grs in inflammation, highlighting their role in cytokine induction and processing.

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A Role for Granzyme M in TLR4-Driven Inflammation and Endotoxicosis

Abstract: Material

Cited by 82 publications

References 44 publications

Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis

Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis

Mouse granzyme K has pro-inflammatory potential

Granzymes Regulate Proinflammatory Cytokine Responses

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