Journal article

Publication year: 2018

Pages: E1530-E1539

Journal: Proceedings of the National Academy of Sciences

Volume number: 115

Issue number: 7

ISSN: 0027-8424

Open access status: Hybrid

DOI Link: https://doi.org/10.1073/pnas.1716095115

Publisher: National Academy of Sciences

Abstract: 
Activation of the NLRP3 inflammasome induces maturation of IL-1 beta and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active ss-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1 ss and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3. In LPS-stimulated human blood-derived macrophages, OLT1177 decreased IL-1 ss levels by 60% and IL-18 by 70% at concentrations 100-fold lower in vitro than plasma concentrations safely reached in humans. OLT1177 also reduced IL-1 ss release and caspase-1 activity in freshly obtained human blood neutrophils. In monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), OLT1177 inhibited LPS-induced IL-1 ss release by 84% and 36%. Immunoprecipitation and FRET analysis demonstrated that OLT1177 prevented NLRP3-ASC, as well as NLRP3-caspase-1 interaction, thus inhibiting NLRP3 inflammasome oligomerization. In a cell-free assay, OLT1177 reduced ATPase activity of recombinant NLRP3, suggesting direct targeting of NLRP3. Mechanistically, OLT1177 did not affect potassium efflux, gene expression, or synthesis of the IL-1 ss precursor. Steady-state levels of phosphorylated NF-.B and IkB kinase were significantly lowered in spleen cells from OLT1177-treated mice. We observed reduced IL-1 ss content in tissue homogenates, limited oxidative stress, and increased muscle oxidative metabolism in OLT1177-treated mice challenged with LPS. Healthy humans receiving 1,000mg of OLT1177 daily for 8 d exhibited neither adverse effects nor biochemical or hematological changes.

Harvard Citation style: Marchetti, C., Swartzwelter, B., Gamboni, F., Neff, C., Richter, K., Azam, T., et al. (2018) OLT1177, a ß-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation, Proceedings of the National Academy of Sciences, 115(7), pp. E1530-E1539. https://doi.org/10.1073/pnas.1716095115

APA Citation style: Marchetti, C., Swartzwelter, B., Gamboni, F., Neff, C., Richter, K., Azam, T., Carta, S., Tengesdal, I., Nemkov, T., D'Alessandro, A., Henry, C., Jones, G., Goodrich, S., Laurent, J., Jones, T., Scribner, C., Barrow, R., Altman, R., Skouras, D., ...Dinarello, C. (2018). OLT1177, a ß-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proceedings of the National Academy of Sciences. 115(7), E1530-E1539. https://doi.org/10.1073/pnas.1716095115