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SP0013 S100-alarmins: potential therapeutic targets for arthritis
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  1. J. Roth
  1. Inst. of Immunology, University of Münster, Münster, Germany

Abstract

Innate immunity is a pivotal factor in the pathogenesis of rheumatic diseases During the last years there is growing evidence that pro-inflammatory alarmins of the family of calcium-binding S100-proteins promote inflammation in rheumatic, auto-inflammatory and auto-immune diseases. Serum concentrations of S100A8/S100A9 correlate with disease activity in several rheumatic diseases and are useful surrogate markers for monitoring disease activity predicting response to treatment, systemic organ involvement, or relapses in several autoimmune diseases. We have now identified a novel mechanism of auto-inhibition in mice and man restricting S100-alarmin activity to local sites of inflammation. We identified specific peptide sequences within the second calcium-binding EF-hands of S100A8 and S100A9 binding to TLR4/MD2 and triggering inflammation. However, biological activity of S100A8/S100A9 is locally restricted by calcium-induced (S100A8/S100A9)2-tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase. This auto-inhibitory mechanism is essential to prevent fatal inflammation in mice in vivo. Since S100A8/S100A9 complexes are the most abundant alarmins in arthritis, blocking of active S100A8/S100A9-dimers may represent an innovative approach for local inhibition of inflammatory processes in rheumatic diseases.

Disclosure of Interest None declared

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