PMID- 27385778
OWN - NLM
STAT- MEDLINE
DCOM- 20170802
LR  - 20210608
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 197
IP  - 4
DP  - 2016 Aug 15
TI  - Active Caspase-1 Induces Plasma Membrane Pores That Precede Pyroptotic Lysis and 
      Are Blocked by Lanthanides.
PG  - 1353-67
LID - 10.4049/jimmunol.1600699 [doi]
AB  - Canonical inflammasome activation induces a caspase-1/gasdermin D 
      (Gsdmd)-dependent lytic cell death called pyroptosis that promotes antimicrobial 
      host defense but may contribute to sepsis. The nature of the caspase-1-dependent 
      change in plasma membrane (PM) permeability during pyroptotic progression remains 
      incompletely defined. We assayed propidium(2+) (Pro(2+)) influx kinetics during 
      NLRP3 or Pyrin inflammasome activation in murine bone marrow-derived macrophages 
      (BMDMs) as an indicator of this PM permeabilization. BMDMs were characterized by 
      rapid Pro(2+) influx after initiation of NLRP3 or Pyrin inflammasomes by 
      nigericin (NG) or Clostridium difficile toxin B (TcdB), respectively. No Pro(2+) 
      uptake in response to NG or TcdB was observed in Casp1(-/-) or Asc(-/-) BMDMs. 
      The cytoprotectant glycine profoundly suppressed NG and TcdB-induced lysis but 
      not Pro(2+) influx. The absence of Gsdmd expression resulted in suppression of 
      NG-stimulated Pro(2+) influx and pyroptotic lysis. Extracellular La(3+) and 
      Gd(3+) rapidly and reversibly blocked the induced Pro(2+) influx and markedly 
      delayed pyroptotic lysis without limiting upstream inflammasome assembly and 
      caspase-1 activation. Thus, caspase-1-driven pyroptosis requires induction of 
      initial prelytic pores in the PM that are dependent on Gsdmd expression. These PM 
      pores also facilitated the efflux of cytosolic ATP and influx of extracellular 
      Ca(2+) Although lanthanides and Gsdmd deletion both suppressed PM pore activity 
      and pyroptotic lysis, robust IL-1beta release was observed in lanthanide-treated 
      BMDMs but not in Gsdmd-deficient cells. This suggests roles for Gsdmd in both 
      passive IL-1beta release secondary to pyroptotic lysis and in nonlytic/nonclassical 
      IL-1beta export.
CI  - Copyright (c) 2016 by The American Association of Immunologists, Inc.
FAU - Russo, Hana M
AU  - Russo HM
AD  - Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
FAU - Rathkey, Joseph
AU  - Rathkey J
AD  - Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
FAU - Boyd-Tressler, Andrea
AU  - Boyd-Tressler A
AUID- ORCID: 0000-0003-4209-2188
AD  - Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106; 
      and.
FAU - Katsnelson, Michael A
AU  - Katsnelson MA
AD  - Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
FAU - Abbott, Derek W
AU  - Abbott DW
AUID- ORCID: 0000-0003-4387-8094
AD  - Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
FAU - Dubyak, George R
AU  - Dubyak GR
AUID- ORCID: 0000-0001-9720-4226
AD  - Department of Pathology, Case Western Reserve University, Cleveland, OH 44106; 
      Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106; 
      and Department of Physiology and Biophysics, Case Western Reserve University, 
      Cleveland, OH 44106 george.dubyak@case.edu.
LA  - eng
GR  - R01 GM036387/GM/NIGMS NIH HHS/United States
GR  - T32 HL105338/HL/NHLBI NIH HHS/United States
GR  - T32 AI089474/AI/NIAID NIH HHS/United States
GR  - P01 DK091222/DK/NIDDK NIH HHS/United States
GR  - R01 EY014362/EY/NEI NIH HHS/United States
GR  - P30 DK097948/DK/NIDDK NIH HHS/United States
GR  - R01 GM086550/GM/NIGMS NIH HHS/United States
GR  - T32 GM007250/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20160706
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Gsdmd protein, mouse)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Lanthanoid Series Elements)
RN  - 0 (Phosphate-Binding Proteins)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
MH  - Animals
MH  - Apoptosis Regulatory Proteins/*metabolism
MH  - Caspase 1/*metabolism
MH  - Cell Membrane/pathology
MH  - Inflammasomes/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Intracellular Signaling Peptides and Proteins
MH  - Lanthanoid Series Elements/pharmacology
MH  - Macrophages/immunology/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phosphate-Binding Proteins
MH  - Pyroptosis/*physiology
PMC - PMC4976007
MID - NIHMS794569
COIS- Conflict of Interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2016/07/08 06:00
MHDA- 2017/08/03 06:00
PMCR- 2017/08/15
CRDT- 2016/07/08 06:00
PHST- 2016/04/20 00:00 [received]
PHST- 2016/06/04 00:00 [accepted]
PHST- 2016/07/08 06:00 [entrez]
PHST- 2016/07/08 06:00 [pubmed]
PHST- 2017/08/03 06:00 [medline]
PHST- 2017/08/15 00:00 [pmc-release]
AID - jimmunol.1600699 [pii]
AID - 10.4049/jimmunol.1600699 [doi]
PST - ppublish
SO  - J Immunol. 2016 Aug 15;197(4):1353-67. doi: 10.4049/jimmunol.1600699. Epub 2016 
      Jul 6.