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Croker, Ben

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Croker

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Ben

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Croker, Ben
Author's Publications: search.filters.isAuthorOfPublication.38fd616d-cc4d-42dd-a4a7-94afcc7dfaac

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    Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia
    (Impact Journals LLC, 2017) McArthur, Kate; D’Cruz, Akshay A.; Segal, David; Lackovic, Kurt; Wilks, Andrew F.; O’Donnell, Joanne A.; Nowell, Cameron J.; Gerlic, Motti; Huang, David C.S.; Burns, Christopher J.; Croker, Ben
    Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38. The parallel screening of kinase inhibitors revealed that mouse and human neutrophil viability is dependent on cyclin-dependent kinase (CDK) activity but surprisingly only partially dependent on PI3 kinase and JAK/STAT signaling, revealing dominant pathways contributing to neutrophil viability. Mcl-1 haploinsufficiency sensitized neutrophils to CDK inhibition, demonstrating that Mcl-1 is a direct target for CDK inhibitors. This study reveals a therapeutic window for the kinase inhibitors BEZ235, BMS-3, AZD7762, and (R)-BI-2536 to induce apoptosis of leukemia cell lines whilst maintaining immunocompetence and hemostasis.
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    Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β
    (The Rockefeller University Press, 2015) Kim, Man Lyang; Chae, Jae Jin; Park, Yong Hwan; De Nardo, Dominic; Stirzaker, Roslynn A.; Ko, Hyun-Ja; Tye, Hazel; Cengia, Louise; DiRago, Ladina; Metcalf, Donald; Roberts, Andrew W.; Kastner, Daniel L.; Lew, Andrew M.; Lyras, Dena; Kile, Benjamin T.; Croker, Ben; Masters, Seth L.
    Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1β, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.
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    RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL
    (Nature Pub. Group, 2015) Lawlor, Kate E.; Khan, Nufail; Mildenhall, Alison; Gerlic, Motti; Croker, Ben; D’Cruz, Akshay A.; Hall, Cathrine; Kaur Spall, Sukhdeep; Anderton, Holly; Masters, Seth L.; Rashidi, Maryam; Wicks, Ian P.; Alexander, Warren S.; Mitsuuchi, Yasuhiro; Benetatos, Christopher A.; Condon, Stephen M.; Wong, W. Wei-Lynn; Silke, John; Vaux, David L.; Vince, James E.
    RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3–caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1β inflammatory responses independent of MLKL and necroptotic cell death.