Abstract
Innate immunity achieves our primary host defense by recognizing invading microorganisms through pathogen-associated molecular patterns (PAMPs) and by reacting to tissue damage signals called damage-associated molecular patterns (DAMPs). DAMP molecules, including high mobility group box 1 protein (HMGB-1), heat-shock proteins (HSPs), uric acid, altered matrix proteins, and S100 proteins, represent important danger signals that mediate inflammatory responses through the receptor for advanced glycation end-products (RAGE, also known as AGER) and Toll-like receptors, after release from activated or necrotic cells. The terms 'alarmins' and 'endokines' have also been proposed for DAMP molecules. A prototypic DAMP molecule, the nuclear protein HMGB-1, is either passively released by necrotic cells or actively secreted with delay by activated cells. S100A8, S100A9, and S100A12 are calcium-binding proteins expressed in the cytoplasm of phagocytes. They are rapidly secreted by activated monocytes or neutrophils, which are abundant in inflamed synovial tissue. HSPs are involved in the crosstalk between innate and adaptive immune systems, and primarily mediate immune regulatory functions. Multiple positive feedback loops between DAMPs and PAMPs and their overlapping receptors temporally and spatially drive these processes and may represent the molecular basis for the observation that infections, as well as nonspecific stress factors, can trigger flares in rheumatic diseases.
Key Points
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The innate immune system, as well as the adaptive immune system, has a key role in initiating and perpetuating synovial inflammation by responding to groups of macromolecules that represent a recognition pattern for potential threats to the host
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Owing to their similarities to cytokines and their release by activated or damaged cells under conditions of cell stress, the terms 'endokines', 'alarmins', or 'danger signals' have been used as synonyms for proinflammatory damage-associated molecular pattern molecules (DAMPs)
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DAMPs include high mobility group box 1 protein (HMGB-1), heat-shock proteins, uric acid, altered matrix proteins, S100 proteins, and a growing number of molecules associated with cell stress and necrosis
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As opposed to pathogen-associated molecular patterns (PAMPs), comprised of pathogen-derived factors, DAMPs represent endogenous molecules that are also ligands for pattern recognition receptors (PRRs)
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The multiligand receptor for advanced glycation end-products (RAGE) and Toll-like receptors are PRRs, which are involved in transducing signals after binding DAMP molecules
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The overlapping receptor systems of DAMPs and PAMPs may represent the molecular basis for the well-known link between nonspecific inflammatory triggers like infections and disease flares in autoimmune disorders
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Foell, D., Wittkowski, H. & Roth, J. Mechanisms of Disease: a 'DAMP' view of inflammatory arthritis. Nat Rev Rheumatol 3, 382–390 (2007). https://doi.org/10.1038/ncprheum0531
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DOI: https://doi.org/10.1038/ncprheum0531
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