Research Projects

Inflammasomes are protein platforms linking recognition of microbe, pathogen and danger associated molecular patterns by cytosolic innate immune sensory proteins such as the Nod-like receptor (NLR) containing a pyrin domain (PYD) NLRP3 to activation of the pro-inflammatory caspase-1. Consequently, active caspase-1 promotes the proteolytic maturation and secretion of the pro-inflammatory cytokines interleukin (IL)-1b and IL-18 and the induction of pyroptotic cell death. Ultimately, this contributes to the initiation of an inflammatory host response directed towards infectious agents and tissue damage by promoting pathogen clearance and wound healing. Dysregulated inflammasome activation contributes to the pathogenesis of a broad range of inflammatory diseases, including Familial Mediterranean Fever, Cryopyrinopathies, gouty arthritis, rheumatoid arthritis, silicosis, asbestosis, atherosclerosis, diabetes, Alzheimer’s disease, multiple sclerosis, asthma, psoriasis, inflammatory bowel disease, cancer, kidney dysfunction, and others. Despite the clear association between inflammasome dysregulation and these diseases, the precise mechanisms controlling inflammasome activation remain poorly understood. Even though inflammasomes are of utmost importance in homeostasis and disease, the underlying mechanisms are still poorly understood, but will be crucial for the design of novel and better treatments. • In this application, we propose to identify a novel regulatory step in inflammasome activation and investigate how the inflammasome response propagates thereby perpetuating the inflammatory cascade. While gene knockout mice are a reliable tool to study inflammasome responses, there are numerous human inflammasome components that are absent in mice and have therefore not been studied in detail. Hence, there are still open questions about human inflammasome regulation. • Our approach to address the problem: NLRP11 bridges the central adaptor ASC to NLRP3 and is necessary for NLRP3 oligomerization to nucleate ASC polymerization. This ternary complex is required for inflammasome assembly and cytokine secretion. Consequently, knock-out (KO) of NLRP11 in human macrophage phenocopies NLRP3 KO. Importantly, NLRP11 is absolutely required for cytokine release driven by NLRP3 mutations that cause Cryopyrin-Associated Periodic Syndrome (CAPS). The objective of this application is to define the mechanism by which NLRP11 promotes NLRP3 inflammasome responses. Our hypothesis is that NLRP11 is required for human NLRP3 inflammasome assembly. This research will improve human health, as it will help us to better understand the complex regulatory mechanisms that maintain homeostasis and a well-balanced inflammatory response in humans. • Our rationale is that unraveling molecular mechanism leading to human inflammasome activation will allow the design of novel modulators that can be targeted for improved treatment strategies to ultimately benefit patients.