Sterile inflammation is significantly driven by endogenous triggers, so called
alarmins, which are released during cellular stress or cell damage. We have
previously shown that the pro-inflammatory alarmins MRP8 and MRP14
promote inflammation via binding to TLR4. Expression of MRP8/MRP14 is
closely associated with disease activity in autoinflammatory diseases and
both proteins are the most abundant pro-inflammatory factors in SJIA, FMF
and PAPA syndrome. We have unpublished preliminary data that complex
formation of MRP8 and MRP14 is of functional relevance for their proinflammatory
activity. Tetramerization interferes with pro-inflammatory
activities of these molecules. In the present project we will define the
molecular structures and signalling pathways involved in MRP-triggered
leukocyte activation using knock-out and knock-in cell models relevant for
MRP-induced leukocyte activation including receptor binding studies. To this
effect we will use genetically modified murine leukocyte cell lines lacking
either MRPs or relevant receptor(s) or signal transduction molecules. Using
targeted mutagenesis of MRP8 and/or MRP14 we will define specific
functions of different complex forms of MRP8/MRP14 by comparative
bioinformatics analyses of genome-wide response patterns. Our final goal is
the characterization of MRP-driven molecular mechanisms of
autoinflammation. In this way will define novel targets for future therapeutic
approaches for treatment of autoinflammatory disorders.