LPS/ATP-induced Peritonitis Model of NLRP3 Inflammasome Activation

Inflammasomes are defined as cytosolic multi-protein complexes that mediate activation of caspase-1 leading to the maturation and secretion of IL-1β and IL-18 and pyroptosis, a bacterial infection-induced form of cell death. Many autoimmune pathologies such as rheumatoid arthritis and lupus have been linked to dysregulation of caspase-1 activation and IL-1β secretion strengthening the need for animal models to study the efficacy of compounds targeting the inflammasomes in vivo. NLRP3 is the best characterised and most clinically implicated inflammasome and is activated in the presence of two specific signals. The first of these signals (priming signal) activates the pathway that leads to upregulation of NLPR3 proteins, pro-IL-1β and pro-IL-18. The second signal is necessary for the assembly of the inflammasome and caspase-1 activation.

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At Charles River we have characterised a clinically relevant acute in vivo model to study the NLRP3 pathway using a combination of LPS and ATP. LPS acts as the priming signal leading to an increase in pro-IL-1β synthesis, but limited increase in mature IL-1β. ATP acts as the second signal and leads to the NLRP3 inflammasome activation that, together with the increased in pro-IL-1β, results in maturation and release of the pro-inflammatory cytokine IL-1β. The increase in IL-1β in peritoneal wash and serum can be reversed by administration of the corticosteroid Dexamethasone and NLRP3-inhibitor compounds. The increase in serum IL-18 can be reversed by NLRP3-inhibitor compounds.

Study parameters include serum and peritoneal wash cytokine analysis.

Study Endpoints

  • Cytokine analyses in serum and peritoneal wash
  • PK/PD blood analyses
  • Clinical chemistry

Validation Data

A NLRP3 inhibitor and Dexamethasone inhibit the inflammasome-induced release of IL-1β in peritoneal
wash and serum. Only NLRP3 inhibition results in a significant reduction in serum IL-18.

A NLRP3 inhibitor and Dexamethasone inhibit the inflammasome-induced release of IL-1β in peritoneal
wash and serum. Only NLRP3 inhibition results in a significant reduction in serum IL-18.

A NLRP3 inhibitor and Dexamethasone inhibit the inflammasome-induced release of IL-1β in peritoneal wash and serum. Only NLRP3 inhibition results in a significant reduction in serum IL-18.