The research focus of my team is to improve our understanding on the role of inflammasomes in autoinflammation after stroke.

The inflammasome is a cytosolic multi-protein complex that assembles in response to specific pattern recognition receptors (PRRs) detecting damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). Once assembled, the inflammasome activates caspase-1, which proteolytically cleaves proinflammatory cytokines and the pore-forming protein Gasdermin D. Inflammasomes drive non-transcriptional inflammatory responses and were initially thought to play a critical role in rapid microbial clearance. However, evidence, including our research on inflammasomes in stroke, burns, and myocardial infarction (MI), indicates that inflammasome activation also occurs in response to tissue injury and other severe stress conditions.

In the context of stroke, inflammasome activation contributes to secondary systemic inflammation, marked by elevated circulating IL-1 levels and significant lymphocyte depletion, which increases susceptibility to secondary infections (Roth et al., 2021, *Immunity*). This effect can be mitigated by IL-1 neutralization or caspase-1 inhibition. Additionally, inflammasome activation after stroke promotes recurrent ischemic events by accelerating atherosclerosis. In this setting, rising levels of cell-free double-stranded DNA (dsDNA) trigger inflammasome activation, leading to increased IL-1 release, which exacerbates plaque instability and contributes to atherothrombosis (Cao & Roth et al., 2024, *Nature*).

Building on our previous work, our aim is to identify the key mediators that activate inflammasomes after stroke and other tissue injuries, as well as their sources. Furthermore, we seek to understand the mechanisms by which stroke-derived ligands are internalized and recognized by cytosolic inflammasome sensors.