Background/Purpose: Acute gout is a highly common and painful form of inflammatory arthritis, occurring mainly in men above the age of 50. The recurring flares of arthritis are elicited by monosodium urate (MSU) crystal deposits in the joints that, in the presence of a secondary stimulus, can induce synergistic cytokine production. Sodium butyrate can inhibit MSU-induced cytokine production via broad inhibition of class I histone deacetylases (HDACs)¹, which includes HDAC1, -2, -3, and -8. HDACs could therefore be an important target for new therapies against gout. Our aim is to further pinpoint the HDAC(s) involved in MSU-induced cytokine production.

Methods: Primary peripheral blood mononuclear cells were isolated from healthy donors. The cells were pre-incubated with a highly specific HDAC1/2 inhibitor, Romidepsin, or other metabolic inhibitors and stimulated with a combination of palmitic acid (C16.0) and MSU crystals. Cytokine levels were measured by ELISA, transcription was measured with qPCR. In vivo effects of Romidepsin were assessed in C57Bl/6 mice. The mice received 2 intraperitoneal doses of Romidepsin, after which we injected them intra-articularly with a MSU crystals and a TLR2 ligand. Joint swelling was assessed macroscopically, IL-6 and KC were measured in the synovium, and total joints were sent for histology.

Results: Romidepsin potently inhibited C16.0+MSU-induced inflammatory cytokines in healthy volunteers. It furthermore induced transcription of PTEN, a negative regulator of PI3K/Akt signaling, and CPT1A, a β-oxidation enzyme that is down-regulated by Akt. Additionally, inhibiting glycolysis with 2-deoxy-D-glucose decreased C16.0+MSU-induced cytokine production, and inhibition of β-oxidation with etomoxir increased it. In vivo, Romidepsin potently inhibits macroscopic joint swelling already at a dose of 0.03 mg/kg. IL-6 and KC were not significantly reduced in the synovium. We are still awaiting the histology results.

Conclusion: These results suggest that Romidepsin inhibits MSU-induced cytokine production by restoring cellular energy homeostasis, possibly by inhibiting Akt signaling. In a relevant mouse model for gout, Romidepsin significantly inhibits macroscopic joint swelling. With these results, we provide a rationale for HDAC1/2 inhibition as a potent anti-inflammatory treatment which may have beneficial effects in acute gout.

References 1. Cleophas MC, Crisan TO, Lemmers H, et al. Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases. Ann Rheum Dis 2015.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppression-of-monosodium-urate-crystal-induced-cytokine-production-via-inhibition-of-histone-deacetylases-12/