Orphan nuclear receptor Nur77 is involved in caspase-independent macrophage cell death.
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.
Kim
Sung Ouk
SO
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
Ono
Koh
K
Tobias
Peter S
PS
Han
Jiahuai
J
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D064326:MEF2 Transcription Factors; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018006:Myogenic Regulatory Factors; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D018805:Sepsis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D064326:MEF2 Transcription Factors; D008562:Membrane Glycoproteins; D018006:Myogenic Regulatory Factors; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases