VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity.

Abstract

The inflammasome is a specialized multiprotein oligomer that regulates IL-1β 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-1β. VU0155069 also significantly blocked IL-1β 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.

• Authors: Sung Kyun Lee, Ye Seon Kim, Geon Ho Bae, Ha Young Lee, Yoe-Sik Bae
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 14349 (10 04 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31586128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Benzimidazoles
• IL1B protein, mouse
• Inflammasomes
• Interleukin-1beta
• Lipopolysaccharides
• N-(1-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo(d)imidazol-1-yl)piperidin-1-yl)propan-2-yl)-2-naphthamide
• Piperidines
• Reactive Oxygen Species
• Phospholipase D
• phospholipase D1
• Caspase 1

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Benzimidazoles (pharmacology, therapeutic use)
• Caspase 1 (metabolism)
• Disease Models, Animal
• Humans
• Inflammasomes (antagonists & inhibitors, immunology, metabolism)
• Interleukin-1beta (metabolism)
• Lipopolysaccharides (immunology)
• Mice
• Mice, Knockout
• Phospholipase D (antagonists & inhibitors, genetics)
• Piperidines (pharmacology, therapeutic use)
• Pyroptosis (drug effects, immunology)
• Reactive Oxygen Species (metabolism)
• Sepsis (drug therapy, immunology, pathology)
• Signal Transduction (drug effects, immunology)