Rare variants of the gene encoding IL-37 have been discovered that result in loss of the cytokine’s anti-inflammatory effects and confer predisposition to gout, with additional evidence suggesting that recombinant IL-37 could have therapeutic potential in the disease. “This is a completely new finding in the field of gout and IL-37 biology,” notes corresponding author Leo Joosten.
IL-1β-mediated inflammation is central to the pathogenesis of gout. The IL-1 family member IL-37 is known to be a negative regulator of IL-1β signalling, and its anti-inflammatory properties have been demonstrated in numerous disease models. However, the contribution of IL-37 to the disease process in gout was unclear.
In the present study, the researchers identified four distinct rare variants of IL37 in six patients with gout (within the discovery cohort of 675 patients) using molecular inversion probe-based resequencing technology. The four variants were clustered in exon 5, which encodes the functional domain of IL-37. None of the variants was found in a control cohort of 520 healthy adults.
The researchers also observed that the patients who were carriers of the rare IL37 variants had either onset of gout at a younger age or a more severe disease phenotype, with multiple inflammatory comorbidities, compared with non-carriers. Predictive modelling and in vitro studies confirmed that the variants affect the structure of the IL-37 protein and consequently its anti-inflammatory function.
In monosodium urate (MSU)-stimulated polymorphonuclear cells from a patient carrying one of the four rare variants, treatment with recombinant IL-37 reduced the production of IL-8 and reactive oxygen species. Moreover, in a mouse model of arthritis, administration of recombinant IL-37 dampened the inflammation induced by MSU crystals in wild-type mice.
administration of recombinant IL-37 dampened the inflammation induced by MSU crystals
“We are planning to perform experiments to treat mice with an IL-37 fusion protein,” says Joosten. If those experiments prove successful, the researchers plan to undertake clinical studies to evaluate the treatment in patients with gout.
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Original article
Klück, V. et al. Rare genetic variants in interleukin-37 link this antiinflammatory cytokine to the pathogenesis and treatment of gout. Ann. Rheum. Dis. https://doi.org/10.1136/annrheumdis-2019-216233 (2020)
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Onuora, S. IL-37 linked to gout pathogenesis and treatment. Nat Rev Rheumatol 16, 250 (2020). https://doi.org/10.1038/s41584-020-0410-8
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DOI: https://doi.org/10.1038/s41584-020-0410-8