Abstract
Background: The cryopyrin-associated periodic syndromes (CAPS) are a group of inherited disorders associated with systemic auto-inflammation. CAPS result from gain-of-function mutations in NLRP3, which result in formation of an intracellular protein complex known as the NLRP3 inflammasome. This leads to overproduction of IL-1β and other pro-inflammatory signals, resulting in inflammatory symptoms. Treatments for NLRP3-related diseases are biologic agents that directly target IL-1β. We sought to determine if the orally available small molecule NLRP3 inhibitor MCC950 could inhibit IL-1β ex vivo in a cohort of patients with autoinflammatory disease. Methods: Patients were recruited to donate blood, from which PBMCs were isolated and assayed in the presence of MCC950 to determine inhibitory efficacy. Results: We found that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and mature IL-1β was higher in ex vivo PBMCs from CAPS patients than healthy donors. MCC950 inhibited production of mature IL-1β in PBMC from CAPS patients with a range of mutations and blocked NLRP3 activity in an in vitro mutation reconstitution assay. Similar results were observed with PBMC from two patients with Schnitzler’s Syndrome, another auto-inflammatory disease. Conclusions: The NLRP3 inflammasome inhibitor MCC950 blocked constitutive activation of NLRP3 observed in the PBMCs of CAPS patients. This study highlights the potential utility of NLRP3 inhibition by a small molecule for rare autoinflammatory diseases that are driven by NLRP3.
Highlights
Families of highly conserved pattern recognition receptors (PRRs) have evolved to occupy cellular membranes and cytosolic compartments of certain immune cells such as macrophages and dendritic cells
This study provides evidence of the efficacy of MCC950 in the inhibition of aberrant IL-1β production with a broad range of ex vivo samples from the largest cohort of cryopyrin-associated periodic syndromes (CAPS) patients reported to date, and for the first time investigates the ex vivo efficacy of an NLRP3 inhibitor in other auto-inflammatory diseases that are characterised by elevated IL-1β levels
NLRP3 requires two signals for activation in healthy donor PBMCs, a priming signal to upregulate the expression of NLRP3 inflammasome machinery and the pro form of IL-1β, and a secondary signal to stimulate processing of IL-1β to its mature form
Summary
Families of highly conserved pattern recognition receptors (PRRs) have evolved to occupy cellular membranes and cytosolic compartments of certain immune cells such as macrophages and dendritic cells. A subset of intracellular receptors denoted Nod-like receptors (NLRs) assemble and oligomerize to form multiprotein intracellular complexes called inflammasomes which can initiate a caspase-1 dependent cascade leading to the production of pro-inflammatory cytokines IL-1β and IL-181. CAPS result from gain-of-function mutations in NLRP3, which result in formation of an intracellular protein complex known as the NLRP3 inflammasome. This leads to overproduction of IL-1β and other pro-inflammatory signals, resulting in inflammatory symptoms. Results: We found that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and mature IL-1β was higher in ex vivo PBMCs from CAPS patients than healthy donors. MCC950 inhibited production of mature IL-1β in PBMC from CAPS patients with a range of mutations and blocked NLRP3 activity in an in vitro mutation reconstitution assay.
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