Jordan Yaron studies the regulation and targeted, therapeutic modulation of caspases by serpins (serine protease inhibitors). Specifically, he is interested in the regulation of caspase-1, a proinflammatory caspase-activated by the inflammasome. The inflammasome is a multiprotein caspase-1-activating complex that regulates the body’s response to infection and injury.
Activation of the inflammasome results in the processing and release of the potent inflammatory cytokines interleukin-1beta and interleukin-18 and proceeds towards an inflammatory cell death called pyroptosis. Dysregulation of the inflammasome pathway can result in sterile disease, such as gouty arthritis or Alzheimer’s, and gain-of-function mutation can cause lifelong periodic fevers that begin early in childhood such as the cryopyrin-associated periodic fever syndromes (CAPS) and neonatal-onset multiple inflammatory disease (NOMID).
Therapeutic targeting of the inflammasome has gained immense popularity as the most widely activated version of this pathway, the NLRP3 inflammasome, has become perhaps the best-characterized immunological therapeutic target known.
Yaron's research focuses on three key questions:
“What is the mechanism of caspase regulation by serpins?”
“How is the inflammasome involved in the pathogenesis of liver diseases?”
“Can immune-modulating serpins be used to treat liver disease?”
Liver Ischemia-reperfusion Injury
Ischemia-reperfusion injury (IRI) is associated with a wide range of severe pathologies and drives the devastating effects of acute transplant rejection and post-surgical complications. IRI is characterized by a two-step process. First, an initial, transient blockade of blood flow and oxygen delivery occurs (ischemia). During this period, sub-lethal injury to tissue occurs. In the second stage of IRI, restoration of blood flow (reperfusion) occurs followed by a paradoxical acceleration of injury.
The reperfusion stage of IRI initiates aggressive, prolonged inflammation leading to tissue damage, organ failure and can even precipitate multiorgan dysfunctions and death. While several potential treatments are being tested in preclinical and Phase I/II trials, there are currently no effective treatments for IRI. One potential limitation in identifying effective treatments for IRI is the complex nature of the pathology. The destructive inflammatory cell activity in IRI is part of an aberrant innate immune response triggering multiple pathways, including apoptosis, necrosis, and the inflammasome, leading to pyroptosis. Thus, single pathway inhibition may be insufficient to limit the tissue destruction in IRI and a multi-pathway approach may be preferred.
Serp-2 is a Myxomavirus-derived immune modulator that inhibits the inflammasome and apoptosis pathways. Serp-2 is a cross-class serine protease inhibitor (serpin) that targets caspase (CASP)-1, CASP8, CASP10 and granzyme B (GzmB). These targets have all been implicated in the pathogenesis of IRI in various tissues, thus Serp-2 is a promising therapeutic for IRI. In a recent study (Yaron et al., Journal of Inflammation 2019), recombinant Serp-2 treatment, given every other day, significantly increased 10-day survival after 90 minutes ischemia, as well as reduced serum levels of ALT and improved tissue viability associated with a reduction of macrophage infiltration (Figure 1).
Figure 1. Recombinant Serp-2 protects in a mouse model of liver IRI. Serp-2 (A) improves 10-day survival, (B) reduces serum 24hr serum ALT levels and (C,D) reduces infarct scar thickness with improved liver viability after IRI in WT C57BL6/J mice. Adapted from Yaron et al., Journal of Inflammation 2019, 16(1), 12.