VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity

• Published in: Scientific reports Vol. 9; no. 1; pp. 14349 - 10
• Main Authors: Lee, Sung Kyun, Kim, Ye Seon, Bae, Geon Ho, Lee, Ha Young, Bae, Yoe-Sik
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.10.2019; Nature Publishing Group
• Subjects: 13/51; 13/95; 14/19; 631/250/256/1980; 631/250/256/2177; 64/60; 692/4017; AKT protein; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Apoptosis; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Bone marrow; Calcium (mitochondrial); Caspase; Caspase 1 - metabolism; Caspase-1; Cecum; Cell activation; Disease Models, Animal; Humanities and Social Sciences; Humans; IL-1β; Inflammasomes; Inflammasomes - antagonists & inhibitors; Inflammasomes - immunology; Inflammasomes - metabolism; Inflammatory diseases; Interleukin-1beta - metabolism; Lipopolysaccharides; Lipopolysaccharides - immunology; Macrophages; MAP kinase; Mice; Mice, Knockout; Mitochondria; multidisciplinary; NF-κB protein; Nigericin; Oligomerization; Phospholipase D - antagonists & inhibitors; Phospholipase D - genetics; Phospholipase D1; Piperidines - pharmacology; Piperidines - therapeutic use; Pyroptosis; Pyroptosis - drug effects; Pyroptosis - immunology; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Sepsis; Sepsis - drug therapy; Sepsis - immunology; Sepsis - pathology; Signal Transduction - drug effects; Signal Transduction - immunology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-50806-9

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.