Key Points Colchicine induces a neutrophil contractile response in a GEF-H1–dependent manner. Colchicine induces GEF-H1–dependent inhibition of neutrophil rolling and adhesion. GEF-H1 is required for colchicine inhibition of neutrophil response to MSU in vivo. Gout is a painful arthritic inflammatory disease caused by buildup of monosodium urate (MSU) crystals in the joints. Colchicine, a microtubule-depolymerizing agent that is used in prophylaxis and treatment of acute gout flare, alleviates the painful inflammatory response to MSU crystals. Using i.p. and intra-articular mouse models of gout-like inflammation, we found that GEF-H1/GEF-H1/AHRGEF2, a microtubule-associated Rho-GEF, was necessary for the inhibitory effect of colchicine on neutrophil recruitment. GEF-H1 was required for neutrophil polarization in response to colchicine, characterized by uropod formation, accumulation of F-actin and myosin L chain at the leading edge, and accumulation of phosphorylated myosin L chain, flotillin-2, and P-selectin glycoprotein ligand-1 (PSGL-1) in the uropod. Wild-type neutrophils that were pre-exposed to colchicine failed to roll or accumulate on activated endothelial monolayers, whereas GEF-H1 knockout (GEF-H1−/−) neutrophils were unaffected by treatment with colchicine. In vivo, colchicine blocked MSU-induced recruitment of neutrophils to the peritoneum and the synovium in wild-type mice, but not in GEF-H1−/− mice. Inhibition of macrophage IL-1β production by colchicine was independent of GEF-H1, supporting a neutrophil-intrinsic mode of action. Our results suggest that the anti-inflammatory effects of colchicine in acute gout-like inflammation can be accounted for by inhibition of neutrophil-rolling interactions with the inflamed vasculature and occurs through GEF-H1–dependent neutrophil stimulation by colchicine. These results contribute to our understanding of the therapeutic action of colchicine, and could inform the application of this drug in other conditions.

中文翻译：

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GEF-H1 是秋水仙碱抑制痛风小鼠模型中性粒细胞滚动和募集所必需的

关键点秋水仙碱以 GEF-H1 依赖性方式诱导中性粒细胞收缩反应。秋水仙碱诱导 GEF-H1 依赖性抑制中性粒细胞滚动和粘附。GEF-H1 是秋水仙碱在体内抑制中性粒细胞对 MSU 的反应所必需的。痛风是一种疼痛性关节炎炎症性疾病，由关节中尿酸单钠 (MSU) 晶体的积聚引起。秋水仙碱是一种用于预防和治疗急性痛风发作的微管解聚剂，可减轻对 MSU 晶体的疼痛炎症反应。使用痛风样炎症的 ip 和关节内小鼠模型，我们发现 GEF-H1/GEF-H1/AHRGEF2，一种微管相关的 Rho-GEF，对于秋水仙碱对中性粒细胞募集的抑制作用是必要的。GEF-H1 是响应秋水仙碱的中性粒细胞极化所必需的，其特征在于尾足类动物的形成、F-肌动蛋白和肌球蛋白 L 链在前缘的积累，以及磷酸化肌球蛋白 L 链、flotillin-2 和 P-选择素糖蛋白配体-1（PSGL-1）在尾足类动物中的积累。预先暴露于秋水仙碱的野生型中性粒细胞无法在活化的内皮单层上滚动或积聚，而 GEF-H1 敲除 (GEF-H1-/-) 中性粒细胞不受秋水仙碱处理的影响。在体内，秋水仙碱阻止了 MSU 诱导的中性粒细胞募集到野生型小鼠的腹膜和滑膜，但在 GEF-H1-/- 小鼠中没有。秋水仙碱对巨噬细胞 IL-1β 产生的抑制与 GEF-H1 无关，支持中性粒细胞内在的作用模式。我们的结果表明，秋水仙碱在急性痛风样炎症中的抗炎作用可以通过抑制中性粒细胞滚动与发炎脉管系统的相互作用来解释，并且是通过秋水仙碱对 GEF-H1 依赖性中性粒细胞的刺激而发生的。这些结果有助于我们了解秋水仙碱的治疗作用，并可以为该药物在其他条件下的应用提供信息。