A major research direction in our laboratory is elucidating the mechanisms by which innate immune cells sense danger: tissue injury and pathogen infection and the subsequently triggered inflammatory host response aimed at restoring homeostasis.
This inflammatory innate immune response is crucial for tissue repair and acute and well controlled inflammation is beneficial – however, chronic and inappropriate inflammation is linked to tissue destruction and disease. Therefore, an important goal is to define strategies to limit these excessive and uncontrolled inflammation.
Inflammasomes are protein platforms that link recognition of danger signals to the activation of inflammatory caspases, including caspase-1, caspase-4/-11 and caspase-5 through canonical and non- canonical pathways, respectively. The consequence of activation of these caspases is proteolytic maturation and secretion of the pro-inflammatory cytokine substrates IL-1beta and IL-18 and induction of an inflammatory cell death called pyroptosis. In particular, excessive release of IL- 1beta is directly linked to the pathology of a wide spectrum of inflammatory diseases.
Hence, for developing novel therapies, it is crucial to better understanding inflammasome biology, including the specific function and activation mechanisms of inflammasome activating cytosolic sensors, including Nod-like receptors (NLRs) and AIM2-like receptors (ALRs), as well as the molecular mechanisms by which these sensors are regulated – for example by PYD-only proteins (POPs), CARD-only proteins (COPs) and protein modifications, which is the central focus of our studies.
Our research contributed several key aspects of inflammasome biology and the inflammatory response and generated several unique mouse models for inflammasome studies. We discovered ASC as the essential adaptor for activation of caspase-1, were the first to visualize the endogenous inflammasome platform “speck” in macrophages, and described several mechanisms by which ASC regulates inflammasomes, discovered the NLRP7 inflammasome in human macrophages, discovered POPs and established the POP family of unique inflammasome regulators, described COP and developed an inflammasome-targeting peptide therapy for inflammatory disease.
Below you can find information on currently ongoing studies or view some of the approaches taken in our lab.