Gasdermins are a family of pore-forming proteins that regulate the release of pro-inflammatory cytokine, interleukin-1beta (IL-1beta) from infected or PAMP-stimulated cells. During infection or injury, IL-1{beta} is released by both human and mouse macrophages. IL-1beta release from mouse macrophages is associated with cell death, often termed pyroptosis. Mouse macrophages undergoing pyroptosis assemble an exit channel termed gasdermin D (GSDMD). Both the processing of IL-1beta and the formation of the exit channel are caspase-1 dependent. Here, in bacterial endotoxin, lipopolysaccharide (LPS), treated mouse bone marrow-derived macrophages (BMDMs), we studied the pharmacologic inhibition of the intracellular nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome by OLT1177. BMDMs stimulated with LPS plus the potassium efflux inducer nigericin triggered the formation of the NLRP3 inflammasome. Treatment of these BMDMs with OLT1177 suppressed cell death by 42% and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain)-speck formation by approximately 60%. In addition, OLT1177 dose-dependently inhibited IL-1beta, CCL3, and myeloperoxidase (MPO) secretion and the pore-forming (GSDMD) from LPS-primed BMDMs, suggesting the existence of a vicious cycle controlled by IL-1beta release. Overall, our study demonstrates that OLT1177 prevents IL-1beta release from BMDMs by inhibiting caspase-1 and the conversion of (GSDMD) into its active N-terminal fragment (GSDMD-N). This study thus supports the concept that orally administered OLT1177 can be used to prevent local as well as systemic inflammation in humans.
Pankratz, K. A., Raza, M., Ypil, J., Banks, M., Marchetti, C., Azam, T., Dinarello, C. A., Atif, S. M.
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