PMID- 34949739
OWN - NLM
STAT- MEDLINE
DCOM- 20220408
LR  - 20240204
IS  - 0219-1032 (Electronic)
IS  - 1016-8478 (Print)
IS  - 1016-8478 (Linking)
VI  - 45
IP  - 4
DP  - 2022 Apr 30
TI  - Pan-Caspase Inhibitor zVAD Induces Necroptotic and Autophagic Cell Death in 
      TLR3/4-Stimulated Macrophages.
PG  - 257-272
LID - 10.14348/molcells.2021.0193 [doi]
AB  - In addition to inducing apoptosis, caspase inhibition contributes to necroptosis 
      and/or autophagy depending on the cell type and cellular context. In macrophages, 
      necroptosis can be induced by co-treatment with Toll-like receptor (TLR) ligands 
      (lipopolysaccharide [LPS] for TLR4 and polyinosinic-polycytidylic acid [poly I:C] 
      for TLR3) and a cell-permeable pan-caspase inhibitor zVAD. Here, we elucidated 
      the signaling pathways and molecular mechanisms of cell death. We showed that 
      LPS/zVAD- and poly I:C/zVAD-induced cell death in bone marrow-derived macrophages 
      (BMDMs) was inhibited by receptor-interacting protein kinase 1 (RIP1) inhibitor 
      necrostatin-1 and autophagy inhibitor 3-methyladenine. Electron microscopic 
      images displayed autophagosome/autolysosomes, and immunoblotting data revealed 
      increased LC3II expression. Although zVAD did not affect LPS- or poly I:C-induced 
      activation of IKK, JNK, and p38, it enhanced IRF3 and STAT1 activation as well as 
      type I interferon (IFN) expression. In addition, zVAD inhibited ERK and Akt 
      phosphorylation induced by LPS and poly I:C. Of note, zVAD-induced enhancement of 
      the IRF3/IFN/STAT1 axis was abolished by necrostatin-1, while zVAD-induced 
      inhibition of ERK and Akt was not. Our data further support the involvement of 
      autocrine IFNs action in reactive oxygen species (ROS)-dependent necroptosis, 
      LPS/zVAD-elicited ROS production was inhibited by necrostatin-1, neutralizing 
      antibody of IFN receptor (IFNR) and JAK inhibitor AZD1480. Accordingly, both cell 
      death and ROS production induced by TLR ligands plus zVAD were abrogated in STAT1 
      knockout macrophages. We conclude that enhanced TRIF-RIP1-dependent autocrine 
      action of IFNbeta, rather than inhibition of ERK or Akt, is involved in 
      TLRs/zVAD-induced autophagic and necroptotic cell death via the JAK/STAT1/ROS 
      pathway.
FAU - Chen, Yuan-Shen
AU  - Chen YS
AUID- ORCID: 0000-0001-8215-7041
AD  - Department of Neurosurgery, National Taiwan University Hospital Yunlin Branch, 
      Douliu 64041, Taiwan.
FAU - Chuang, Wei-Chu
AU  - Chuang WC
AUID- ORCID: 0000-0001-8181-1099
AD  - Department of Pharmacology, College of Medicine, National Taiwan University, 
      Taipei 10617, Taiwan.
FAU - Kung, Hsiu-Ni
AU  - Kung HN
AUID- ORCID: 0000-0001-6979-8346
AD  - Graduate Institute of Anatomy and Cell Biology, National Taiwan University, 
      Taipei 10617, Taiwan.
FAU - Cheng, Ching-Yuan
AU  - Cheng CY
AUID- ORCID: 0000-0001-9251-7549
AD  - Department of Pharmacology, College of Medicine, National Taiwan University, 
      Taipei 10617, Taiwan.
FAU - Huang, Duen-Yi
AU  - Huang DY
AUID- ORCID: 0000-0002-2787-1346
AD  - Department of Pharmacology, College of Medicine, National Taiwan University, 
      Taipei 10617, Taiwan.
FAU - Sekar, Ponarulselvam
AU  - Sekar P
AUID- ORCID: 0000-0003-4282-2865
AD  - Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 11031, 
      Taiwan.
FAU - Lin, Wan-Wan
AU  - Lin WW
AUID- ORCID: 0000-0002-3207-734X
AD  - Department of Pharmacology, College of Medicine, National Taiwan University, 
      Taipei 10617, Taiwan.
AD  - Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 11031, 
      Taiwan.
AD  - Department of Pharmacology, National Defense Medical Center, Taipei 11490, 
      Taiwan.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Mol Cells
JT  - Molecules and cells
JID - 9610936
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Ligands)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Toll-Like Receptor 3)
RN  - 25249-22-3 (Poly I)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - *Autophagic Cell Death
MH  - Caspase Inhibitors/metabolism/pharmacology
MH  - Caspases/metabolism
MH  - Ligands
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophages
MH  - Poly I/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - *Toll-Like Receptor 3/metabolism
PMC - PMC9001149
OTO - NOTNLM
OT  - JAK/STAT1
OT  - autophagy
OT  - interferon
OT  - macrophage
OT  - necrosis
OT  - zVAD
COIS- CONFLICT OF INTEREST The authors have no potential conflicts of interest to 
      disclose.
EDAT- 2021/12/25 06:00
MHDA- 2022/04/09 06:00
PMCR- 2021/12/20
CRDT- 2021/12/24 05:36
PHST- 2021/07/23 00:00 [received]
PHST- 2021/09/24 00:00 [revised]
PHST- 2021/10/15 00:00 [accepted]
PHST- 2021/12/25 06:00 [pubmed]
PHST- 2022/04/09 06:00 [medline]
PHST- 2021/12/24 05:36 [entrez]
PHST- 2021/12/20 00:00 [pmc-release]
AID - S1016-8478(23)00096-1 [pii]
AID - molce-45-4-257 [pii]
AID - 10.14348/molcells.2021.0193 [doi]
PST - ppublish
SO  - Mol Cells. 2022 Apr 30;45(4):257-272. doi: 10.14348/molcells.2021.0193.