Speaker
Description
Introduction: Hereditary autoinflammatory diseases (AID) are a group devastating disorders characterized by chronic inflammation and unprovoked activation of phagocytes. Classical AIDs are caused by mutations in the NLRP3-inflammasome, leading to excess of IL-1β-release, whereas inflammation in non-classical AID (ncAID), e. g. PAPA- (Pyogenic sterile Arthritis, Pyoderma gangrenosum, Acne) and PAMI- (PSTPIP1-Associated Myeloid-related-Proteinaemia Inflammatory) syndrome has been linked to mutations in the PSTPIP1 and Pyrin genes and to an extraordinary overexpression of S100A8 and S100A9 in phagocytes. S100A8/A9 can be released by tubulin-dependent alternative secretory pathways to induce pro-inflammatory effects through interaction with Toll-like receptor 4 (TLR-4).
Objectives: The aim of the present project is to analyze the mechanisms in which ncAID associated PSTPlP1 mutations lead to an exaggerated S100 secretion.
Materials & methods: Monocytes of PAMI patients were isolated, and S100A8/A9 levels were measured in culture supernatants prior and after activation. PSTPIP1-Pyrin-S100A8/A9 interactions were investigated by co-immunoprecipitation, immunofluorescence- and ELISA studies.
Results: Our studies demonstrate that PSTPIP1 and pyrin interact with the S100A8-S100A9 complex. Moreover in PSTPIP1 we could map the respective binding site to the CC domain bearing disease associated mutations. Monocytes from patients carrying PSTPIP1 mutations showed an exaggerated release of S100A8/A9.
Conclusion: S100A8/A9 are highly oversecreted in FMF-, PAPA- and PAMI patients. Pyrin and PSTPIP1 interact directly with S100A8 and S100A9 pointing towards an important role of them in the alternative secretion of those proteins. Moreover PSTPIP1 mutations found in all patients are restricted to the S00A8/A9 binding region and these PSTPIP1 mutations also influence the interaction with pyrin. Overall, our data indicate that hypersecretion of S100A8/A9 is a relevant pathomechanism in PSTPIP1- and pyrin-associated diseases.
