Chemokines in rheumatic diseases: pathogenic role and therapeutic implications

Abstract

Chemokines, a family of small secreted chemotactic cytokines, and their G protein-coupled seven transmembrane spanning receptors control the migratory patterns, positioning and cellular interactions of immune cells. The levels of chemokines and their receptors are increased in the blood and within inflamed tissue of patients with rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis or idiopathic inflammatory myopathies. Chemokine ligand–receptor interactions control the recruitment of leukocytes into tissue, which are central to the pathogenesis of these rheumatic diseases. Although the blockade of various chemokines and chemokine receptors has yielded promising results in preclinical animal models of rheumatic diseases, human clinical trials have, in general, been disappointing. However, there have been glimmers of hope from several early-phase clinical trials that suggest that sufficiently blocking the relevant chemokine pathway might in fact have clinical benefits in rheumatic diseases. Hence, the chemokine system remains a promising therapeutic target for rheumatic diseases and requires further study.

Key points

  • Chemokines are a large family of secreted chemotactic cytokines that control the recruitment of immune cells into tissue and their cellular interactions once in tissue.

  • Chemokine receptors are G protein-coupled seven transmembrane spanning proteins that are expressed on immune cells and regulate their migration and cell–cell interactions.

  • Concentrations of chemokines are increased in the blood and tissues of patients with rheumatic diseases, suggesting their involvement in the pathogenesis of these diseases and highlighting them as therapeutic targets.

  • Preclinical animal models of rheumatic diseases show the important functional roles of the chemokine system in the pathogenesis of these diseases.

  • Unfortunately, the majority of clinical trials testing the efficacy of chemokine and chemokine receptor inhibitors have failed to show meaningful clinical benefit.

  • However, several clinical studies have shown promise and suggest that targeting the relevant chemokine system and ensuring complete inhibition at all times might be needed for therapeutic benefit.

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Fig. 1: Chemokines and chemokine receptors in RA.
Fig. 2: Chemokines and chemokine receptors in systemic lupus erythematosus.
Fig. 3: Chemokines and chemokine receptors in systemic sclerosis.
Fig. 4: Chemokines and chemokine receptors in giant cell arteritis.
Fig. 5: Chemokines and chemokine receptors in idiopathic inflammatory myositis.

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Acknowledgements

The work of Y.M. is supported by the Japanese Society for the Promotion of Science (JSPS) Kakenhi grant number JP19K08895, the Takeda Science Foundation, the Maruyama Memorial Research Foundation and the Medical Research Encouragement Prize of the Japan Medical Association. The work of A.D.L. is supported by grants from the National Institutes of Health and the Rheumatology Research Foundation.

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Y.M. researched data for this article. Y.M. and A.D.L. provided substantial contributions to discussions of content. Y.M., J.L., C.M. and A.D.L. wrote this article and reviewed and/or edited the manuscript before submission.

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Correspondence to Andrew D. Luster.

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Miyabe, Y., Lian, J., Miyabe, C. et al. Chemokines in rheumatic diseases: pathogenic role and therapeutic implications. Nat Rev Rheumatol 15, 731–746 (2019). https://doi.org/10.1038/s41584-019-0323-6

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