PMID- 34582774
OWN - NLM
STAT- MEDLINE
DCOM- 20220106
LR  - 20220106
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 193
DP  - 2021 Nov
TI  - Volume-activated chloride channels contribute to lipopolysaccharide plus 
      nigericin-induced pyroptosis in bone marrow-derived macrophages.
PG  - 114791
LID - S0006-2952(21)00407-X [pii]
LID - 10.1016/j.bcp.2021.114791 [doi]
AB  - The representative morphological features of pyroptosis are excessive cell 
      swelling and subsequent membrane rupture. However, the mechanism underlying the 
      cell's inherent inability to regulate volume during the progression of pyroptosis 
      is poorly understood. In the current study, we found that both volume-activated 
      chloride currents (I(cl, vol)) and the regulatory volume decrease (RVD) were 
      markedly decreased in bone marrow-derived macrophages (BMDMs) undergoing 
      pyroptosis induced by lipopolysaccharides (LPS) and nigericin. The inhibition of 
      I(Cl, vol) and RVD by the chloride channel blockers, tamoxifen or DCPIB, led to 
      the emergence of pyroptosis-like phenotypes such as activated-caspase-1, 
      pyroptotic-body-like bubbles, and a fried-egg-like appearance. Moreover, the 
      expression of the volume-activated chloride channel (VRAC) constituent protein 
      Leucine-Rich Repeat-Containing 8A (LRRC8A) was significantly down-regulated in 
      pyroptotic BMDMs treated with LPS and nigericin. The silencing of LRRC8A 
      expression by small interfering RNA (si)-LRRC8A transfection not only reduced 
      I(Cl, vol) and RVD, but also caused BMDMs to show pyroptosis-like manifestations 
      such as activated-caspase-1, membrane bubbles, and have a fried-egg-like 
      appearance. These results reveal a new mechanism for the loss of volume 
      regulation in the process of pyroptotic cell swelling and strongly suggest that a 
      functional deficiency of VRAC/LRRC8A plays a key role in this disorder.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Ye, Xiaomin
AU  - Ye X
AD  - Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances and 
      School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical 
      University, Guangzhou 510006, PR China.
FAU - Liu, Xiaoyong
AU  - Liu X
AD  - Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances and 
      School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical 
      University, Guangzhou 510006, PR China.
FAU - Wei, Wenjun
AU  - Wei W
AD  - Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances and 
      School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical 
      University, Guangzhou 510006, PR China.
FAU - Yu, Huiping
AU  - Yu H
AD  - Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances and 
      School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical 
      University, Guangzhou 510006, PR China.
FAU - Jin, Xiaobao
AU  - Jin X
AD  - Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances and 
      School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical 
      University, Guangzhou 510006, PR China.
FAU - Yu, Jinwei
AU  - Yu J
AD  - Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances and 
      School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical 
      University, Guangzhou 510006, PR China.
FAU - Li, Chunmei
AU  - Li C
AD  - Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances and 
      School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical 
      University, Guangzhou 510006, PR China.
FAU - Xu, Bin
AU  - Xu B
AD  - Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances and 
      School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical 
      University, Guangzhou 510006, PR China.
FAU - Guo, Xinmin
AU  - Guo X
AD  - Department of Ultrasound, Guangzhou Red Cross Hospital, Medical College, Jinan 
      University, Guangzhou, Guangdong 510220, PR China. Electronic address: 
      guo8186@126.com.
FAU - Mao, Jianwen
AU  - Mao J
AD  - Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances and 
      School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical 
      University, Guangzhou 510006, PR China. Electronic address: 
      jianwenmao@gdpu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210925
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-one-5-yl)oxybutyric acid)
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Biomarkers)
RN  - 0 (Chloride Channels)
RN  - 0 (Cyclopentanes)
RN  - 0 (Estrogen Antagonists)
RN  - 0 (Indans)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - RRU6GY95IS (Nigericin)
SB  - IM
MH  - Animals
MH  - Anti-Bacterial Agents/toxicity
MH  - Biomarkers
MH  - Chloride Channels/*metabolism
MH  - Cyclopentanes/pharmacology
MH  - Estrogen Antagonists/pharmacology
MH  - Gene Expression Regulation/drug effects
MH  - Indans/pharmacology
MH  - Lipopolysaccharides/*toxicity
MH  - Macrophages
MH  - Male
MH  - Membrane Proteins
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nigericin/*toxicity
MH  - Pyroptosis/*drug effects
MH  - RNA, Small Interfering
MH  - Tamoxifen/pharmacology
OTO - NOTNLM
OT  - Chloride channel
OT  - LRRC8A
OT  - Pyroptosis
OT  - Regulatory volume decrease
EDAT- 2021/09/29 06:00
MHDA- 2022/01/07 06:00
CRDT- 2021/09/28 20:13
PHST- 2021/08/25 00:00 [received]
PHST- 2021/09/17 00:00 [revised]
PHST- 2021/09/24 00:00 [accepted]
PHST- 2021/09/29 06:00 [pubmed]
PHST- 2022/01/07 06:00 [medline]
PHST- 2021/09/28 20:13 [entrez]
AID - S0006-2952(21)00407-X [pii]
AID - 10.1016/j.bcp.2021.114791 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2021 Nov;193:114791. doi: 10.1016/j.bcp.2021.114791. Epub 2021 
      Sep 25.