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TNFα-induced macrophage death via caspase-dependent and independent pathways

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Abstract

Macrophages are the principal source of TNFα, yet they are highly resistant to TNFα-mediated cell death. Previously, employing in vitro differentiated human macrophages, we showed that following the inhibition of NF-κB, TNFα-induced caspase-8 activation contributes to DNA fragmentation but is not necessary for the loss of the inner mitochondrial transmembrane potential (ΔΨm) or cell death. We here extend these observations to demonstrate that, when NF-κB is inhibited in macrophages, TNFα alters lysosomal membrane permeability (LMP). This results in the release of cathepsin B with subsequent loss of ΔΨm and caspase-8 independent cell death. Interestingly, the cytoprotective, NF-κB-dependent protein A20 was rapidly induced in macrophages treated with TNFα. Ectopic expression of A20 in macrophages preserves LMP following treatment with TNFα, and as a result, mitochondrial integrity is safeguarded and macrophages are protected from cell death. These observations demonstrate that TNFα triggers both caspase 8-dependent and -independent cell death pathways in macrophages and identify a novel mechanism by which A20 protects these cells against both pathways.

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Acknowledgments

This work was partly funded by R01 grants from the NIH: AR049217 and AR048269 to RMP and DK063275 and HL080130 to CF.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron St., Suite M300, Chicago, IL, 60611, USA

    Tri M. Tran, Vladislav Temkin, Bo Shi, Lisa Pagliari & Richard M. Pope

  2. Division of Vascular Surgery and Nephrology, Departments of Surgery and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Soizic Daniel & Christiane Ferran

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  1. Tri M. Tran
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  2. Vladislav Temkin
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Correspondence to Richard M. Pope.

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Tri M. Tran and Vladislav Temkin have contributed equally to this manuscript.

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Tran, T.M., Temkin, V., Shi, B. et al. TNFα-induced macrophage death via caspase-dependent and independent pathways. Apoptosis 14, 320–332 (2009). https://doi.org/10.1007/s10495-009-0311-4

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