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S100 proteins in rheumatic diseases

Abstract

Rheumatic diseases are characterized by sterile inflammation that causes severe long-term damage to various organ systems. A growing body of evidence supports a pivotal role for the pro-inflammatory calcium-binding S100 family of proteins in the pathogenesis of rheumatic diseases. Some S100 proteins are released at the site of inflammation and act as danger-associated molecular pattern molecules by activating pattern recognition receptors. Increased concentrations of S100 proteins in serum and synovial fluid closely correlate with disease activity in several rheumatic diseases and serve as useful biomarkers for monitoring disease activity. Some S100 proteins are also valid biomarkers for predicting response to treatment, systemic organ involvement or disease flares in rheumatic diseases. Analyses of knockout mouse models have confirmed a functional role for S100 proteins, particularly S100A8 and S100A9, in rheumatic diseases, indicating that blocking the expression, release or function of these proteins might be an innovative therapeutic strategy. Owing to their local pattern of expression, specific mechanism of release and autoregulatory effects, such therapeutic approaches would primarily target the local inflammatory process and present only minor risks of systemic adverse effects.

Key points

  • S100 proteins are expressed abundantly and released at local sites of inflammation, making them functionally relevant in the pathogenesis of rheumatic diseases.

  • S100 proteins are well-established biomarkers of inflammation and disease progression in several rheumatic diseases.

  • S100 proteins have been targeted effectively in experimental preclinical models and in preliminary clinical trials to treat autoimmune diseases.

  • Targeting the mechanism of S100 protein secretion and the immunomodulatory effects of S100 proteins are promising approaches for future therapeutic strategies.

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Fig. 1: Intracellular and extracellular functions of S100 proteins.
Fig. 2: S100A8–S100A9 signalling pathways.
Fig. 3: Targeting S100 protein functions as potential therapies.
Fig. 4: Induction of innate and adaptive immune tolerance by S100 proteins.

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Acknowledgements

The work of the authors is supported by grants to the Innovative Medical Research of the University of Münster (AU121327 and AU211603 to J.A.), the Interdisciplinary Center of Clinical Research at the University of Münster (Ro2/003/15 to J.R.), the German Research Foundation (DFG) (CRC1009 B8 and Z2 to J.R.), ERARE2 network Treat-AID and the Federal Ministry of Education and Research (BMBF) (project AID-NET to J.R.).

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Austermann, J., Spiekermann, C. & Roth, J. S100 proteins in rheumatic diseases. Nat Rev Rheumatol 14, 528–541 (2018). https://doi.org/10.1038/s41584-018-0058-9

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