PMID- 35130622
OWN - NLM
STAT- MEDLINE
DCOM- 20220316
LR  - 20230211
IS  - 1745-7270 (Electronic)
IS  - 1672-9145 (Print)
IS  - 1672-9145 (Linking)
VI  - 54
IP  - 1
DP  - 2022 Jan 25
TI  - Induction of multiple subroutines of regulated necrosis in murine macrophages by 
      natural BH3-mimetic gossypol.
PG  - 64-76
LID - 10.3724/abbs.2021004 [doi]
AB  - Macrophages are critical sentinel cells armed with multiple regulated necrosis 
      pathways, including pyroptosis, apoptosis followed by secondary necrosis, and 
      necroptosis, and are poised to undergo distinct form(s) of necrosis for tackling 
      dangers of pathogenic infection or toxic exposure. The natural BH3-mimetic 
      gossypol is a toxic phytochemical that can induce apoptosis and/or 
      pyroptotic-like cell death, but what exact forms of regulated necrosis are 
      induced remains largely unknown. Here we demonstrated that gossypol induces 
      pyroptotic-like cell death in both unprimed and lipopolysaccharide-primed mouse 
      bone marrow-derived macrophages (BMDMs), as evidenced by membrane swelling and 
      ballooning accompanied by propidium iodide incorporation and lactic acid 
      dehydrogenase release. Notably, gossypol simultaneously induces the activation of 
      both pyroptotic and apoptotic (followed by secondary necrosis) pathways but only 
      weakly activates the necroptosis pathway. Unexpectedly, gossypol-induced necrosis 
      is independent of nucleotide-binding oligomerization domain-like receptor family 
      pyrin domain containing 3 (NLRP3) inflammasome, as neither inhibitor for the 
      NLRP3 pathway nor NLRP3 deficiency protects the macrophages from the necrosis. 
      Furthermore, necrotic inhibitors or even pan-caspase inhibitor alone does not or 
      only partly inhibit such necrosis. Instead, a combination of inhibitors composed 
      of pan-caspase inhibitor IDN-6556, RIPK3 inhibitor GSK'872 and NADPH oxidase 
      inhibitor GKT137831 not only markedly inhibits the necrosis, with all apoptotic 
      and pyroptotic pathways being blocked, but also attenuates gossypol-induced 
      peritonitis in mice. Lastly, the activation of the NLRP3 pathway and apoptotic 
      caspase-3 appears to be independent of each other. Collectively, gossypol 
      simultaneously induces the activation of multiple subroutines of regulated 
      necrosis in macrophages depending on both apoptotic and inflammatory caspases.
FAU - Zhong, Meiyan
AU  - Zhong M
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Huang, Yuanting
AU  - Huang Y
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Zeng, Bo
AU  - Zeng B
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Xu, Lihui
AU  - Xu L
AD  - Department of Cell Biology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Zhong, Chunsu
AU  - Zhong C
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Qiu, Jiahao
AU  - Qiu J
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Ye, Xunjia
AU  - Ye X
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Chen, Mingye
AU  - Chen M
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Hu, Bo
AU  - Hu B
AD  - Department of Nephrology, the First Affiliated Hospital of Jinan University, 
      Guangzhou 510632, China.
FAU - Ouyang, Dongyun
AU  - Ouyang D
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - He, Xianhui
AU  - He X
AD  - Department of Immunobiology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
LA  - eng
PT  - Journal Article
PL  - China
TA  - Acta Biochim Biophys Sin (Shanghai)
JT  - Acta biochimica et biophysica Sinica
JID - 101206716
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - EC 3.4.22.36 (Caspase 1)
RN  - KAV15B369O (Gossypol)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Caspase 1/metabolism
MH  - *Gossypol/metabolism/pharmacology
MH  - Inflammasomes/metabolism
MH  - Macrophages/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Necrosis/chemically induced/metabolism
PMC - PMC9909304
OTO - NOTNLM
OT  - BH3-mimetic
OT  - gossypol
OT  - macrophages
OT  - necroptosis
OT  - pyroptosis
OT  - secondary necrosis
COIS- The authors declare that they have no conflict of interest.
EDAT- 2022/02/08 06:00
MHDA- 2022/03/17 06:00
PMCR- 2021/12/21
CRDT- 2022/02/07 20:05
PHST- 2022/02/07 20:05 [entrez]
PHST- 2022/02/08 06:00 [pubmed]
PHST- 2022/03/17 06:00 [medline]
PHST- 2021/12/21 00:00 [pmc-release]
AID - 10.3724/abbs.2021004 [doi]
PST - ppublish
SO  - Acta Biochim Biophys Sin (Shanghai). 2022 Jan 25;54(1):64-76. doi: 
      10.3724/abbs.2021004.