Equipe Berenbaum - Nefla M et al. Nat Rev Rheumatology. 2016.

13 - Septembre - 2016

The danger from within: alarmins in arthritis. Nat Rev Rheumatology. 2016.


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.

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

Meriam Nefla, Dirk Holzinger, Francis Berenbaum & Claire Jacques Nature Reviews Rheumatology volume 12, pages 669–683 (2016)

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