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.
Highlights
Inflammatory cytokines such as IL-1β, TNF-α, and IL-6 play crucial roles to mediate the pathological progression of diverse infectious or inflammatory diseases[1]
Since we found that VU0155069 administration blocks IL-1β production from the spleen in cecal ligation and puncture (CLP) mice (Fig. 1E) and inflammasome activation is apparent in macrophages, we examined the effects of the phospholipase D1 (PLD1) inhibitor VU0155069 on inflammasome activation in macrophages
In this study we found that administration of VU0155069, an inhibitor of PLD1, effectively induces therapeutic effects against experimental polymicrobial sepsis
Summary
Inflammatory cytokines such as IL-1β, TNF-α, and IL-6 play crucial roles to mediate the pathological progression of diverse infectious or inflammatory diseases[1]. These inflammatory cytokines are produced by several immune cells and inflammatory cells, and contribute to further recruitment of inflammatory cells into injured or event areas leading to tissue and organ damage[2]. MCC950 and BHB, inhibit the NLRP3 inflammasome by blocking ASC oligomerization[9] Some autophagy inducers such as resveratrol and the CB2R agonist show inhibitory effects against the NLRP3 inflammasome[10]. We investigated the effects of a PLD1-selective inhibitor, VU0155069 on the regulation of inflammation and inflammasome
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