Molecular Role of Bruton’s Tyrosine Kinase (BTK) in NLRP3 Inflammasome Activation

• Applicant: Professor Alexander Weber, Ph.D.
• Subject Area: Immunology ; Cell Biology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 414795436

The NLRP3 inflammasome has emerged a critical multi-protein complex formed upon exogenous and endogenous (sterile) insults during infection, tissue damage or cellular stress and its assembly has been considered a key process in initiating inflammation. For example, multiple diseases in humans, ranging from Staphylococcal infections to diabetes to ischemic stroke or heart attack, have been linked to the NLRP3 inflammasome. The elucidation of (i) its molecular mechanism of action, (ii) regulatory molecules; and (iii) pharmacological inhibitors are key challenges in immunology and inflammation research at current. We have identified the well-known signaling molecule Bruton’s Tyrosine Kinase (BTK) to unexpectedly play a critical role in NLRP3 inflammasome activation in both mice and humans. Strategies hoping to target the NLRP3 inflammasome are probably years from reaching clinical significance; however, the discovery of BTK as an NLRP3 regulator offers the unique opportunity to target the NLRP3 inflammasome at the level of a well-known pharmacological target, BTK, via efficacious and well-tolerated FDA-approved inhibitors, e.g. ibrutinib (PCI-32765). To safely do so, further vital open questions need to be addressed first: 1) What is the mechanistic molecular and cellular role of BTK in inflammasome activation? Specifically, how are the tyrosine kinase activity of BTK and potential additional functions related to its other protein domains involved in NLRP3 modification, activation and assembly? 2) What is the in vivo significance and therapeutic potential of BTK’s involvement in inflammasome activation in sterile and non-sterile inflammatory states involving the NLRP3 inflammasome? We describe here how we would like to employ in vitro analyses in murine and human primary cells, novel and cell-specific murine in vivo models and patient ex vivo analyses to comprehensively address these questions as detailed in the work program. Our vision is to elucidate the molecular workings of the BTK-NLRP3 inflammasome to a level that will allow for safely harnessing the considerable translational potential of BTK as a targetable NLRP3 regulator.

• DFG Programme: Research Grants