Dissecting cellular interactions underlying auto-inflammation in Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is an auto-inflammatory disease caused by mutations in the gene encoding Pyrin. FMF-associated Pyrin mutants trigger inappropriate inflammasome activation allowing excessive levels of Interleukin (IL)-1β to provoke fever episodes, joint pain, abdominal pain and skin inflammation in FMF patients. We aim to uncover the cellular interactions by which inflammasome- and IL- 1β-induced signaling pathways orchestrate auto-inflammation in FMF. We will employ a genetic approach allowing to abolish either IL-1β production or IL-1β responses in a cell type specific manner in an FMF mouse model, which will experimentally identify these cellular drivers of FMF-related auto-inflammation in mice. In parallel, we will profile single cell transcriptomes as well as cell surface proteins in these FMF mice. This will specifically reveal the gene expression programs of cells displaying the IL-1β receptor on their surface. Guided by this knowledge, inflammasome activation and IL- 1β stimulation experiments will identify IL-1β producing and IL-1β responding cells, respectively, among different types of immune cells obtained from FMF patients. Understanding the cellular level of how inflammasomes and IL-1β cooperate to propel auto-inflammation may facilitate improved therapeutic approaches targeting the driver cell types in FMF, and may uncover common themes that will help to better understand other inflammatory diseases driven by inflammasome and IL-1β signalling.

Keywords:INFLAMMASOME, AUTO-INFLAMMATIE

Disciplines:Inflammation, Cell signalling