Background Familial Mediterranean Fever (FMF) is an auto-inflammatory syndrome caused by mutations within the MEFV gene encoding pyrin protein. The FMF syndromeis associated with activation of phagocytic cells and secretion of IL-1β. The production and secretion of IL-1β is regulated by interactions of pyrin and the NALP3-inflammasome, but exact pathogenic mechanisms are still elusive. Like IL-1β, the pro-inflammatory Damage Associated Molecular Pattern (DAMP) molecules S100A8/A9 are released by a Golgi-independent but tubulin-dependent, so called alternative secretory pathway (1, 2). S100A8/A9 have been recently identified as endogenous activators of TLR4 and several studies on inflammatory disorders demonstrated their potential as biomarkers of inflammation (3).
Objectives Our goal was i) to correlate S100A8/A9 serum concentrations in FMF-patients to disease activity and to evaluate the potential of S100A8/A9 as biomarker, ii) to study S100A8/A9 -pyrin interaction, iii) to analyze S100A8/A9 serum-concentrations in FMF-mice.
Methods 52 genetically proven FMF-patients were studied longitudinally over 18 months. Serum-levels of S100A8/A9 (ELISA), ESR, CRP and SAA were analysed before and during colchicine treatment and compared to other autoinflammatory syndromes. S100A8/A9 serum-levels of homozygous Pyrin V726A knock-in mice (“FMF-mice”) were determined for secretion analysis. Interaction and co-localization of S100A8/A9 and pyrin was analysed by immunofluorescence-, co-immunoprecipitation- and affinity-chromatography experiments.
Results The mean serum-levels of S100A8/A9 during inflammatory episodes of FMF (Mean ± SEM 343,210±202,210 ng/ml) were significantly higher compared to chronic infantile neurological, cutaneous and articular (CINCA) syndrome (2,830±580 ng/ml; p<0.001) or Muckle-Wells syndrome (MWS) (3,205±585 ng/ml; p<0.001), and correlated to disease activity. Similar, sera of homozygous FMF-mice showed increased S100A8/A9 -levels (1,260±540 ng/ml) compared to WT- (150±40 ng/ml), or heterozygous FMF-mice (340±180 ng/ml). Immunofluorescence stainings of human monocytes showed a colocalisation of pyrin, S100A8/A9 and tubulin. Moreover a direct molecular interaction of pyrin with S100A8/A9 could be demonstrated in immunoprecipitation and affinity-chromatographyexperiments.
Conclusions S100A8/A9 are strongly secreted in FMF-patients compared to other IL-1 driven diseases. Measurement of S100A8/A9 -levels in FMF might be a valuable tool to reflect disease activity and response to anti-inflammatory therapy. Pyrin interacts directly with S100A8/A9 pointing towards an important role in the alternative secretion of those proteins in FMF.
Vogl et al. (2007) Nat. Med. 13, 1042-1049.
Rammes et al. (1997) J. Biol. Chem. 272, 9496-9502.
Frosch et al. (2000) Arthritis Rheum. 43, 628-637.
Disclosure of Interest None Declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.