Objective: Gout, induced by monosodium urate (MSU) crystal deposition in joint tissues, provokes severe pain and impacts life quality of patients. However, the mechanisms underlying gout pain are still incompletely understood./nMethods: We established a mouse gout model by intra-articularly injection of MSU crystals into the ankle joint of wild type and genetic knockout mice. RNA-Sequencing, in vivo molecular imaging, Ca²⁺ imaging, reactive oxygen species (ROS) generation, neutrophil influx and nocifensive behavioral assays, etc. were used./nResults: We found interleukin-33 (IL-33) was among the top up-regulated cytokines in the inflamed ankle. Neutralizing or genetic deletion of IL-33 or its receptor ST2 (suppression of tumorigenicity) significantly ameliorated pain hypersensitivities and inflammation. Mechanistically, IL-33 was largely released from infiltrated macrophages in inflamed ankle upon MSU stimulation. IL-33 promoted neutrophil influx and triggered neutrophil-dependent ROS production via ST2 during gout, which in turn, activated transient receptor potential ankyrin 1 (TRPA1) channel in dorsal root ganglion (DRG) neurons and produced nociception. Further, TRPA1 channel activity was significantly enhanced in DRG neurons that innervate the inflamed ankle via ST2 dependent mechanism, which results in exaggerated nociceptive response to endogenous ROS products during gout./nConclusions: We demonstrated a previous unidentified role of IL-33/ST2 in mediating pain hypersensitivity and inflammation in a mouse gout model through promoting neutrophil-dependent ROS production and TRPA1 channel activation. Targeting IL-33/ST2 may represent a novel therapeutic approach to ameliorate gout pain and inflammation.

中文翻译：

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IL-33 / ST2诱导中性粒细胞依赖性活性氧的产生并介导痛风痛

目的：痛风是由尿酸单钠（MSU）晶体沉积在关节组织中引起的，可引起剧烈疼痛并影响患者的生活质量。然而，痛风疼痛的潜在机制仍未完全了解。/n方法：我们通过将MSU晶体关节内注射到野生型和基因敲除小鼠的踝关节中，建立了小鼠痛风模型。使用RNA测序，体内分子成像，Ca ²⁺成像，活性氧（ROS）生成，嗜中性粒细胞流入和伤害行为分析等。/n结果：我们发现白细胞介素33（IL-33）是发炎的脚踝中最上调的细胞因子之一。IL-33或其受体ST2的中和或遗传缺失（致瘤性抑制）显着改善了疼痛过敏和炎症。从机制上讲，在MSU刺激下，IL-33在炎性踝关节中从巨噬细胞浸润的巨噬细胞大量释放。IL-33在痛风期间通过ST2促进中性粒细胞的流入并触发中性粒细胞依赖性ROS的产生，从而激活背根神经节（DRG）神经元中的瞬时受体电位锚蛋白1（TRPA1）通道并产生伤害感受。此外，DRG神经元通过ST2依赖性机制支配发炎的踝关节，TRPA1通道活性显着增强，这导致痛风期间对内源性ROS产物的伤害性反应过度。结论：我们证明了IL-33 / ST2以前在小鼠痛风模型中通过促进中性粒细胞依赖性ROS产生和TRPA1通道激活来介导疼痛超敏反应和炎症的作用尚未确定。靶向IL-33 / ST2可能代表减轻痛风疼痛和炎症的新型治疗方法。