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Highly Efficient Transfection of Human THP-1 Macrophages by Nucleofection
Published on: September 2, 2014
Orphan nuclear receptor Nur77 is involved in caspase-independent macrophage cell death
Sung Ouk Kim1, Koh Ono, Peter S Tobias
1Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
Abstract:
Activation-induced cell death in macrophages has been observed, but the mechanism remains largely unknown. Activation-induced cell death in macrophages can be independent from caspases, and the death of activated macrophages can even be triggered by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD). Here, we show that this type of macrophage death can occur in the septic mouse model and that toll-like receptor (TLR)-2 or TLR4 signaling is required in this process. We conclude that Nur77 is involved in the macrophage death because Nur77 expression correlates with cell death, and cell death is reduced significantly in Nur77-deficient macrophages. The extracellular signal-regulated kinase pathway, which is downstream of TLR2 or TLR4, and myocyte-specific enhancer binding factor 2 (MEF2) transcription factor activity, which is up-regulated by zVAD, are required for Nur77 induction and macrophage death. Reporter gene analysis suggests that Nap, Ets, Rce, and Sp1 sites in the Nur77 promoter are regulated by TLR4 signaling and that MEF2 sites in the Nur77 promoter are regulated by zVAD treatment. MEF2 transcription factors are constitutively expressed and degraded in macrophages, and zVAD increases MEF2 transcription factor activity by preventing the proteolytic cleavage and degradation of MEF2 proteins. This paper delineates the dual signaling pathways that are required for Nur77 induction in macrophages and demonstrates a role of Nur77 in caspase-independent cell death.
Insights
Activation-induced macrophage death, independent of caspases, requires Toll-like receptor (TLR) signaling and the Nur77 protein. This process involves extracellular signal-regulated kinase and MEF2 transcription factor pathways.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Activation-induced cell death (AICD) in macrophages is a known phenomenon, but its underlying mechanisms are not fully understood.
- AICD can occur independently of caspases, as demonstrated by its induction with pan-caspase inhibitors like zVAD.
- The physiological relevance of this caspase-independent AICD in disease models is yet to be elucidated.
Purpose of the Study:
- To investigate the molecular mechanisms driving caspase-independent activation-induced cell death in macrophages.
- To identify key signaling pathways and transcription factors involved in this cell death process.
- To determine the role of Nur77 in macrophage apoptosis and its regulation by Toll-like receptor (TLR) signaling.
Main Methods:
- Utilized a septic mouse model to study macrophage death in vivo.
- Employed genetic deficiency models (Nur77-deficient macrophages) and pharmacological inhibitors (zVAD).
- Investigated signaling pathways including Toll-like receptor (TLR) 2/4, extracellular signal-regulated kinase (ERK), and myocyte-specific enhancer binding factor 2 (MEF2) using reporter gene assays.
Main Results:
- Caspase-independent macrophage death was observed in a septic mouse model, requiring TLR-2 or TLR-4 signaling.
- Nur77 expression strongly correlated with cell death, and its deficiency significantly reduced macrophage death.
- The ERK pathway (downstream of TLRs) and MEF2 transcription factor activity (upregulated by zVAD) were essential for Nur77 induction and subsequent cell death.
Conclusions:
- Nur77 plays a critical role in caspase-independent activation-induced cell death of macrophages.
- Dual signaling pathways, involving TLRs/ERK and zVAD/MEF2, converge to regulate Nur77 induction.
- This study elucidates novel mechanisms of macrophage death relevant to inflammatory and septic conditions.
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