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  • Review Article
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The danger from within: alarmins in arthritis

Nature Reviews Rheumatology volume 12, pages 669–683 (2016)Cite this article

Subjects

Key Points

  • Alarmins are endogenous molecules that are rapidly released to the extracellular milieu during infection and tissue damage, activating receptors such as Toll-like receptors and receptor for advanced glycosylation end products

  • In arthritis, including degenerative joint disease (osteoarthritis (OA)) and chronic inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis and spondylarthropathy), extracellular levels of alarmins are associated with disease activity and joint destruction

  • In OA, S100 proteins and high mobility group protein B1 (HMGB1) are important alarmins that induce positive-feedback loops of synovial cell reactivation, inflammation and cartilage degradation

  • Alarmins involved in chronic inflammatory arthritis include S100 proteins, HMGB1, heat-shock proteins and IL-33; these alarmins represent important links between the innate and adaptive immune systems

  • The level of alarmins in serum and synovial fluid could provide useful diagnostic and prognostic biomarkers of arthritis, and inhibiting alarmin pathways could be a therapeutically beneficial approach

Abstract

Alarmins (also known as danger signals) are endogenous molecules that are released to the extracellular milieu after infection or tissue damage. Extracellular alarmins interact with specific receptors expressed by cells that are engaged in host defence to stimulate signalling pathways that result in initiation of innate and adaptive immune responses, triggering inflammation or tissue repair. Alarmins are considered to be markers of destructive processes that occur in degenerative joint diseases (primarily osteoarthritis (OA)) and chronic inflammatory joint diseases (such as rheumatoid arthritis, psoriatic arthritis and spondylarthropathy). In OA, high mobility group protein B1 (HMGB1) and S100 proteins, along with many other alarmins, are abundantly secreted by joint cells, promoting cartilage matrix catabolism, osteophyte formation, angiogenesis and hypertrophic differentiation. The involvement of alarmins in chronic inflammatory arthritides is suggested by their presence in serum at high levels in these conditions, and their expression within inflamed synovia and synovial fluid. S100 proteins, HMGB1, IL-33 and other endogenous molecules have deleterious effects on joints, and can recruit immune cells such as dendritic cells to inflamed synovia, initiating the adaptive immune response and perpetuating disease. Improving our understanding of the pathological mechanisms associated with these danger signals is important to enable the targeting of new therapeutic approaches for arthritis.

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Figure 1: A schematic, integrative overview of alarmins.
Figure 2: Role of S100 proteins and high mobility group protein B1 in osteoarthritis.
Figure 3: Role of S100 proteins, high mobility group protein B1 and heat-shock proteins in chronic inflammatory arthritis.

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Acknowledgements

The authors were supported by INSERM, the University of Paris 6 (Pierre and Marie Curie), Arthritis R&D (ROAD: Research on Osteoarthritic Diseases) and the Agence Nationale de la Recherche. D.H. acknowledges support from the Interdisciplinary Centre of Clinical Research, Münster, Germany (Clinical Research Award CRA0) and the German Ministry for Education and Science (BMBF 01GM08100, AID-Net).

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Authors and Affiliations

  1. Sorbonne University, UPMC University Paris 06, UMR_S 938, Paris, 75005, France

    Meriam Nefla, Francis Berenbaum & Claire Jacques

  2. INSERM UMR_S938, UPMC University Paris 06, Paris, 75012, France

    Meriam Nefla, Francis Berenbaum & Claire Jacques

  3. Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 184 rue du Faubourg Saint-Antoine, Paris, 75012, France

    Meriam Nefla, Francis Berenbaum & Claire Jacques

  4. Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Domagkstr. 3, Münster, 48149, Germany

    Dirk Holzinger

  5. Department of Rheumatology, Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, 184 rue du Faubourg Saint-Antoine, Paris, 75012, France

    Francis Berenbaum

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All authors contributed equally to researching data for the article, to substantial discussions of its content, to writing the article and to reviewing and editing of the manuscript before submission.

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Correspondence to Francis Berenbaum.

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D.H. declares that he has received speaker's fees from Novartis. M.N., F.B. and C.J. declare no competing interests.

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Nefla, M., Holzinger, D., Berenbaum, F. et al. The danger from within: alarmins in arthritis. Nat Rev Rheumatol 12, 669–683 (2016). https://doi.org/10.1038/nrrheum.2016.162

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