Prolactinomas have harmful effects on human health, and the pathogenesis is still unknown. Furthermore, 25% of prolactinoma patients do not respond to the therapy of dopamine receptor agonist in the clinic. Thus, it is important to reveal the pathogenesis and develop new therapeutic methods for prolactinomas. Herein, two animal models of prolactinomas, namely oestrogen-treated rats and transgenic D2 dopamine receptor-deficient mice, were used. PET/CT imaging detection showed that translocator protein-mediated microglia activation and inflammation significantly increased in the pituitary glands of prolactinomas rats. Messenger RNA microarrays were used to analyze and compare the differential gene and signal pathways of the pituitary glands between control and prolactinomas rats. Statistical results pertaining to gene enrichment showed that the innate immune response genes were upregulated in the pituitary glands of prolactinoma rats. This suggested that the innate immune response was activated. We analyzed the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome that is one of the most important members of the innate immune system in mammals and found that the expressions of NLRP3, Caspase-1, apoptosis-associated speck-like, interleukin 1B (IL1B) and IL18 proteins of pituitary glands in prolactinomas rats were increased considerably compared with those in control rats. This suggested the activation of the NLRP3 inflammasome during the emergence and evolution of prolactinomas. Immunohistochemistry results also confirmed that the NLRP3 expression was elevated in human prolactinoma tissues, and the microglia marker-ionised calcium binding adaptor molecule-1 was co-located with the NLRP3 protein in prolactinomas by immunofluorescence assay. Finally, compared with the WT mice, NLRP3-/- mice had smaller pituitary glands (weight/body weight) and diminished prolactin (PRL) expressions and secretions. These findings were associated with a reduction in the caspase-1 activation and maturation of IL1B. Furthermore, MCC950 decreased the PRL expression and secretion following the inhibition of NLRP3 inflammasome activation in GH3 cells stimulated with lipopolysaccharide and nigericin. And MCC950 inhibited the pituitary tumor overgrowth and PRL expression and secretion in prolactinoma rats. These data confirm that the microglial NLRP3 inflammasome activation upregulates the inflammatory cytokines IL1/IL18 in the pituitary glands and induces prolactinomas. Our findings showed that microglial NLRP3 inflammasome activation-mediated IL1B-related inflammation promoted the development of prolactinomas and identified the inflammasome as a new therapeutic target for prolactinomas.

中文翻译：

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小胶质细胞 NLRP3 炎症小体激活介导的炎症促进泌乳素瘤的发展。

泌乳素瘤对人体健康有危害，发病机制尚不清楚。此外，临床上25%的泌乳素瘤患者对多巴胺受体激动剂的治疗没有反应。因此，揭示泌乳素瘤的发病机制和开发新的治疗方法非常重要。在此，使用了两种泌乳素瘤动物模型，即雌激素治疗的大鼠和转基因 D2 多巴胺受体缺陷小鼠。PET/CT 成像检测显示，易位蛋白介导的小胶质细胞活化和炎症在泌乳素瘤大鼠垂体中显着增加。信使RNA微阵列用于分析和比较对照和泌乳素瘤大鼠之间垂体的差异基因和信号通路。有关基因富集的统计结果表明，先天免疫反应基因在泌乳素瘤大鼠的垂体中上调。这表明先天免疫反应被激活。我们分析了作为哺乳动物先天免疫系统最重要成员之一的 NLRP3（NOD-、LRR- 和 pyrin 结构域蛋白 3）炎症小体，发现 NLRP3、Caspase-1、凋亡相关斑点的表达与对照大鼠相比，催乳素瘤大鼠垂体的类白细胞介素 1B (IL1B) 和 IL18 蛋白显着增加。这表明在泌乳素瘤的出现和演变过程中激活了 NLRP3 炎性体。免疫组织化学结果还证实，人泌乳素瘤组织中 NLRP3 表达升高，并且通过免疫荧光测定，小胶质细胞标志物离子化的钙结合衔接分子-1与泌乳素瘤中的NLRP3蛋白位于同一位置。最后，与 WT 小鼠相比，NLRP3-/- 小鼠的垂体（体重/体重）更小，催乳素 (PRL) 表达和分泌减少。这些发现与 caspase-1 激活和 IL1B 成熟的减少有关。此外，MCC950 在脂多糖和尼日利亚菌素刺激的 GH3 细胞中抑制 NLRP3 炎性体激活后，降低了 PRL 的表达和分泌。MCC950抑制泌乳素瘤大鼠垂体瘤过度生长和PRL的表达和分泌。这些数据证实，小胶质细胞 NLRP3 炎性体激活上调了垂体中的炎性细胞因子 IL1/IL18 并诱导催乳素瘤。我们的研究结果表明，小胶质细胞 NLRP3 炎性体激活介导的 IL1B 相关炎症促进了催乳素瘤的发展，并将炎性体确定为催乳素瘤的新治疗靶点。