Jecure Therapeutics Science

Published work from the lab of Jecure founder Dr. Ariel Feldstein has demonstrated that activation of the NLRP3 inflammasome in mice results in severe liver inflammation, fibrosis, and hepatocyte pyroptotic cell death. Furthermore, in murine models of NASH, NLRP3 activation is required for the fibrotic response, suggesting that targeting this complex may be a rational strategy to block the progression of NASH and reverse fibrosis.

Jecure is developing small-molecule therapeutics to block inflammasome activation and disrupt the sterile inflammation loop that results in hepatocellular injury and cell death.

Sterile Inflammation Loop (Figure 1).

An intrahepatic, self-perpetuating noxious loop is central to NASH development and progression. NLRP3 inflammasome activation plays a key role in each of the components of this loop including induction of pro-inflammatory signaling, hepatocellular injury and cell death, and activation of the hepatic stellate cells (HSC) that are responsible for collagen deposition and liver fibrosis.

Figure 1. Sterile Inflammation Loop. From A. Wree et al., “NLRP3 Activation Results in Hepatocyte Pyroptosis, Liver Inflammation, and Fibrosis in Mice,” Hepatology 2014, 59(3):898-910.

Mechanisms of NLRP3 Inflammasome Activation (Figure 2).

Inflammasome components such as NLRP3, ASC and caspase‐1 are expressed in immune cells in the liver including Kupffer cells, infiltrating macrophages, hepatocytes, and hepatic stellate cells. Inflammasome activation is dependent on two successive signals. Signal 1 (dotted lines), driven by TLR and IL‐1R signaling, includes expression of component proteins including NLRP3, ASC, pro‐caspase‐1, pro‐IL‐1β, and pro‐IL-18. Signal 2 is provided by danger signals (DAMPS) that during NASH development are mainly released by stressed or dying hepatocytes or via a ”leaky” gut (PAMPs). This process leads to oligomerization of the inflammasome components and cleavage of pro-caspase‐1, leading to the release of active pro-inflammatory cytokines.

Abbreviations: DAMP, damage‐associated molecular pattern; PAMP, pathogen‐associated molecular pattern; TLR, Toll‐like receptor.

Figure 2. Mechanisms of NLRP3 Inflammasome Activation. From A. Wree et al., "From NAFLD to NASH to cirrhosis - new insights into disease mechanisms," Nat Rev Gastroenterol. Hepatol. 2013, 10 (11):627-636.