PMID- 31586128
OWN - NLM
STAT- MEDLINE
DCOM- 20201111
LR  - 20210110
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Oct 4
TI  - VU0155069 inhibits inflammasome activation independent of phospholipase D1 
      activity.
PG  - 14349
LID - 10.1038/s41598-019-50806-9 [doi]
LID - 14349
AB  - The inflammasome is a specialized multiprotein oligomer that regulates IL-1beta 
      production. Although regulation of the inflammasome is related to crucial 
      inflammatory disorders such as sepsis, pharmacological inhibitors that 
      effectively inhibit inflammasome activity are limited. Here, we evaluated the 
      effects of a phospholipase D1 (PLD1)-selective inhibitor (VU0155069) against 
      sepsis and inflammasome activation. VU0155069 strongly enhances survival rate in 
      cecal ligation and puncture (CLP)-induced sepsis by inhibiting lung inflammation, 
      leukocyte apoptosis, and the production of proinflammatory cytokines, especially 
      IL-1beta. VU0155069 also significantly blocked IL-1beta production, caspase-1 
      activation, and pyroptosis caused by several inflammasome-activating signals in 
      the bone marrow-derived macrophages (BMDMs). However, VU0155069 did not affect 
      LPS-induced activation of signaling molecules such as MAPK, Akt, NF-kappaB, and NLRP3 
      expression in the BMDMs. VU0155069 also failed to affect mitochondrial ROS 
      generation and calcium increase caused by nigericin or ATP, and subsequent ASC 
      oligomerization caused by several inflammasome-activating signals. VU0155069 
      indirectly inhibited caspase-1 activity caused by LPS + nigericin in BMDMs 
      independent of PLD1 activity. We demonstrated that a PLD1 inhibitor, VU0155069, 
      shows anti-septic activity as well as inflammasome-inhibiting effects. Our 
      results suggest that VU0155069 can be considered a novel inflammasome inhibitor.
FAU - Lee, Sung Kyun
AU  - Lee SK
AUID- ORCID: 0000-0001-8130-7431
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
AD  - Institute for Stem Cell & Regenerative Medicine Research of Albert Einstein 
      College of Medicine, Bronx, NY, 10461, USA.
FAU - Kim, Ye Seon
AU  - Kim YS
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Bae, Geon Ho
AU  - Bae GH
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Lee, Ha Young
AU  - Lee HY
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Bae, Yoe-Sik
AU  - Bae YS
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea. yoesik@skku.edu.
AD  - Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 
      Seoul, 06351, Republic of Korea. yoesik@skku.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191004
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Benzimidazoles)
RN  - 0 (IL1B protein, mouse)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 
      (N-(1-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo(d)imidazol-1-yl)piperidin-1-yl)propan-2-yl)-2-naphthamide)
RN  - 0 (Piperidines)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 3.1.4.4 (Phospholipase D)
RN  - EC 3.1.4.4 (phospholipase D1)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology/therapeutic use
MH  - Benzimidazoles/*pharmacology/therapeutic use
MH  - Caspase 1/metabolism
MH  - Disease Models, Animal
MH  - Humans
MH  - Inflammasomes/*antagonists & inhibitors/immunology/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Lipopolysaccharides/immunology
MH  - Mice
MH  - Mice, Knockout
MH  - Phospholipase D/antagonists & inhibitors/genetics
MH  - Piperidines/*pharmacology/therapeutic use
MH  - Pyroptosis/drug effects/immunology
MH  - Reactive Oxygen Species/metabolism
MH  - Sepsis/*drug therapy/immunology/pathology
MH  - Signal Transduction/drug effects/immunology
PMC - PMC6778193
COIS- The authors declare no competing interests.
EDAT- 2019/10/06 06:00
MHDA- 2020/11/12 06:00
PMCR- 2019/10/04
CRDT- 2019/10/06 06:00
PHST- 2019/05/13 00:00 [received]
PHST- 2019/09/19 00:00 [accepted]
PHST- 2019/10/06 06:00 [entrez]
PHST- 2019/10/06 06:00 [pubmed]
PHST- 2020/11/12 06:00 [medline]
PHST- 2019/10/04 00:00 [pmc-release]
AID - 10.1038/s41598-019-50806-9 [pii]
AID - 50806 [pii]
AID - 10.1038/s41598-019-50806-9 [doi]
PST - epublish
SO  - Sci Rep. 2019 Oct 4;9(1):14349. doi: 10.1038/s41598-019-50806-9.