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  • Review Article
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Innate immune memory in inflammatory arthritis

Abstract

The concept of immunological memory was demonstrated in antiquity when protection against re-exposure to pathogens was observed during the plague of Athens. Immunological memory has been linked with the adaptive features of T and B cells; however, in the past decade, evidence has demonstrated that innate immune cells can exhibit memory, a phenomenon called ‘innate immune memory’ or ‘trained immunity’. Innate immune memory is currently being defined and is transforming our understanding of chronic inflammation and autoimmunity. In this Review, we provide an up-to-date overview of the memory-like features of innate immune cells in inflammatory arthritis and the crosstalk between chronic inflammatory milieu and cell reprogramming. Aberrant pro-inflammatory signalling, including cytokines, regulates the metabolic and epigenetic reprogramming of haematopoietic progenitors, leading to exacerbated inflammatory responses and osteoclast differentiation, in turn leading to bone destruction. Moreover, imprinted memory on mature cells including terminally differentiated osteoclasts alters responsiveness to therapies and modifies disease outcomes, commonly manifested by persistent inflammatory flares and relapse following medication withdrawal.

Key points

  • The failure of adaptive immune suppression to achieve sustained remission in inflammatory arthritis highlights the existence of an innate memory phenotype within the immune joint cellular infiltrate.

  • Pro-inflammatory cytokines can induce innate memory on haematopoietic and progenitor stem cells that exhibit either an increased or an immunosuppressive inflammatory response, resulting in perpetuation or resolution of inflammatory arthritis, respectively.

  • This acquired memory is demonstrated in osteoclast precursors and potentially terminally differentiated osteoclasts that have the capacity to recycle to osteomorphs and produce stronger secondary responses and increased bone resorption under chronic arthritic conditions.

  • Innate immune memory serves as an immunomodulatory factor that contributes to various clinical patterns in inflammatory arthritis such as remission, flares and treatment response rate.

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Fig. 1: Inflammatory imprinting of synovial fibroblasts in arthritis.
Fig. 2: Peripheral inflammation and maladaptive bone marrow myelopoiesis.
Fig. 3: Macrophage immune memory in inflammatory arthritis.
Fig. 4: Memory imprinting of osteoclasts during chronic inflammation.

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Acknowledgements

I.E.A.’s work is supported by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants 2R01AR062173 and R01AR068974.

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Correspondence to Iannis E. Adamopoulos.

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Jeljeli, M.M., Adamopoulos, I.E. Innate immune memory in inflammatory arthritis. Nat Rev Rheumatol 19, 627–639 (2023). https://doi.org/10.1038/s41584-023-01009-0

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