Landis R Clive, Yagnik Darshna R, Florey Oliver, Philippidis Pandelis, Emons Vivien, Mason Justin C, Haskard Dorian O
British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, London, UK.
Arthritis Rheum. 2002 Nov;46(11):3026-33. doi: 10.1002/art.10614.
Although monosodium urate monohydrate (MSU) crystals have been recognized since the 18th century as the etiologic agent of gout, it is still unknown why certain hyperuricemic individuals remain asymptomatic, and how an acute attack of gout spontaneously resolves. We hypothesized that mononuclear phagocytes hold the key to these questions, and that the state of monocyte/macrophage differentiation is critical.
Human peripheral blood monocytes were differentiated for 1-7 days in vitro and examined with respect to 1) uptake of MSU crystals, 2) expression of macrophage, dendritic cell, and activation markers, 3) secretion of tumor necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), IL-6, and IL-10, 4) activation of endothelial E-selectin expression, and 5) enhancement of secondary neutrophil recruitment by endothelial cells.
MSU crystals induced TNFalpha, IL-1beta, and IL-6 (but not IL-10) secretion in undifferentiated monocytes, which in turn promoted endothelial cell E-selectin expression and secondary neutrophil capture under shear flow. In contrast, differentiation over 3-5 days led to development of a noninflammatory phenotype characterized by a lack of proinflammatory cytokine secretion, lack of endothelial cell activation, and lack of secondary neutrophil recruitment. Acquisition of the noninflammatory phenotype correlated with expression of macrophage antigen but not with expression of dendritic cell marker or activation marker. Monocytes and macrophages were similarly phagocytic, and a control particle, zymosan, elicited secretion of the full panel of cytokines in both cell types. However, coincubation with MSU led to a significant suppression of zymosan-induced TNFalpha secretion (P = 0.009) from macrophages but not monocytes.
These findings imply that differentiated macrophages provide a safe-disposal mechanism for the removal of inflammatory urate crystals. This may be of clinical relevance to the maintenance of asymptomatic hyperuricemia and the resolution of acute gout.
尽管自18世纪以来，一水合尿酸钠（MSU）晶体就被认为是痛风的致病因素，但仍不清楚为什么某些高尿酸血症个体没有症状，以及痛风急性发作是如何自发缓解的。我们推测单核吞噬细胞是这些问题的关键，并且单核细胞/巨噬细胞的分化状态至关重要。
将人外周血单核细胞在体外分化1 - 7天，并针对以下方面进行检测：1）MSU晶体的摄取；2）巨噬细胞、树突状细胞和活化标志物的表达；3）肿瘤坏死因子α（TNFα）、白细胞介素1β（IL - 1β）、IL - 6和IL - 10的分泌；4）内皮细胞E - 选择素表达的激活；5）内皮细胞对中性粒细胞二次募集的增强。
MSU晶体在未分化的单核细胞中诱导TNFα、IL - 1β和IL - 6（但不包括IL - 10）的分泌，进而在剪切流作用下促进内皮细胞E - 选择素表达和中性粒细胞的二次捕获。相反，3 - 5天的分化导致一种非炎症表型的形成，其特征为缺乏促炎细胞因子分泌、缺乏内皮细胞活化以及缺乏中性粒细胞的二次募集。非炎症表型的获得与巨噬细胞抗原的表达相关，而与树突状细胞标志物或活化标志物的表达无关。单核细胞和巨噬细胞的吞噬作用相似，并且一种对照颗粒——酵母聚糖，在两种细胞类型中均能引发所有细胞因子的分泌。然而，与MSU共同孵育导致巨噬细胞中酵母聚糖诱导的TNFα分泌显著受抑制（P = 0.009），而单核细胞不受影响。
这些发现表明，分化的巨噬细胞为清除炎性尿酸盐晶体提供了一种安全处理机制。这可能与无症状高尿酸血症的维持以及急性痛风的缓解具有临床相关性。
