VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity.
Sci Rep
; 9(1): 14349, 2019 10 04.
Article
em En
| MEDLINE
| ID: mdl-31586128
ABSTRACT
The inflammasome is a specialized multiprotein oligomer that regulates IL-1ß 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-1ß. VU0155069 also significantly blocked IL-1ß 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-κB, 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Benzimidazóis
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Sepse
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Inflamassomos
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Anti-Inflamatórios
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article