Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs) can significantly reduce MSU crystals-induced inflammation. However, which one of HDACs members in response to MSU crystals was still unknown. Here, we investigated the roles of HDAC3 in MSU crystals-induced gouty inflammation. Macrophage specific HDAC3 knockout (KO) mice were used to investigate inflammatory profiles of gout in mouse models in vivo, including ankle arthritis, foot pad arthritis and subcutaneous air pouch model. In the in vitro experiments, bone marrow-derived macrophages (BMDMs) from mice were treated with MSU crystals to assess cytokines, potential target gene and protein. Deficiency of HDAC3 in macrophage not only reduced MSU-induced foot pad and ankle joint swelling but also decreased neutrophils trafficking and IL-1β release in air pouch models. In addition, the levels of inflammatory genes related to TLR2/4/NF-κB/IL-6/STAT3 signaling pathway were significantly decreased in BMDMs from HDAC3 KO mice after MSU treatment. Moreover, RGFP966, selective inhibitor of HDAC3, inhibited IL-6 and TNF-α production in BMDMs treated with MSU crystals. Besides, HDAC3 deficiency shifted gene expression from pro-inflammatory macrophage (M1) to anti-inflammatory macrophage (M2) in BMDMs after MSU challenge. Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout.

中文翻译：

---

巨噬细胞中组蛋白脱乙酰酶 3 的缺乏可减轻尿酸钠晶体诱导的小鼠痛风炎症


痛风是由尿酸钠 (MSU) 晶体沉积引发免疫反应引起的。最近的一项研究表明，抑制 I 类组蛋白脱乙酰酶 (HDAC) 可以显着减少 MSU 晶体引起的炎症。然而，哪一位 HDAC 成员对 MSU 晶体做出反应仍不得而知。在这里，我们研究了 HDAC3 在 MSU 晶体诱导的痛风炎症中的作用。使用巨噬细胞特异性 HDAC3 敲除 (KO) 小鼠在体内研究小鼠模型中的痛风炎症特征，包括踝关节关节炎、足垫关节炎和皮下气囊模型。在体外实验中，用 MSU 晶体处理小鼠骨髓源性巨噬细胞 (BMDM)，以评估细胞因子、潜在靶基因和蛋白质。巨噬细胞中 HDAC3 的缺乏不仅减少了 MSU 引起的足垫和踝关节肿胀，而且还减少了气囊模型中中性粒细胞的运输和 IL-1β 的释放。此外，MSU治疗后，HDAC3 KO小鼠的BMDM中与TLR2/4/NF-κB/IL-6/STAT3信号通路相关的炎症基因水平显着降低。此外，HDAC3 的选择性抑制剂 RGFP966 抑制用 MSU 晶体处理的 BMDM 中 IL-6 和 TNF-α 的产生。此外，在 MSU 攻击后，HDAC3 缺陷使 BMDM 中的基因表达从促炎巨噬细胞 (M1) 转变为抗炎巨噬细胞 (M2)。巨噬细胞中 HDAC3 的缺乏通过抑制 TLR2/4 驱动的 IL-6/STAT3 信号通路减轻了 MSU 晶体诱导的痛风炎症，这表明 HDAC3 可能有助于痛风的潜在治疗靶点。