Department of Medicine and Surgery, Pharmacology Division, University of Perugia, 06132 Perugia, Italy.
Department of Medicine and Surgery, Medical Microbiology Division, University of Perugia, 06132 Perugia, Italy.
Cells. 2021 Aug 28;10(9):2228. doi: 10.3390/cells10092228.
Glucocorticoids are the most powerful anti-inflammatory and immunosuppressive pharmacological drugs available, despite their adverse effects. Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced gene that shares several anti-inflammatory properties with glucocorticoids. Although immunosuppressive effects of glucocorticoids on neutrophils remain poorly understood, we previously demonstrated that GILZ suppresses neutrophil activation under glucocorticoid treatment. Here, we sought to explore the regulation of Toll-like receptor 2 (TLR2) by the synthetic glucocorticoid dexamethasone (DEX) on neutrophils and the associated GILZ involvement. Peripheral blood neutrophils were isolated from wild type and GILZ-knock-out (KO) mice. TLR2 was found to be downregulated by the in vivo administration of glucocorticoids in wild type but not in GILZ-KO neutrophils, suggesting the involvement of GILZ in TLR2 downregulation. Accordingly, the TLR2-associated anti-fungal activity of neutrophils was reduced by DEX treatment in wild type but not GILZ-KO neutrophils. Furthermore, GILZ did not interact with NF-κB but was found to bind with STAT5, a pivotal factor in the regulation of TLR2 expression. A similar modulation of TLR2 expression, impaired phagocytosis, and killing activity was observed in circulating human neutrophils treated in vitro with DEX. These results demonstrate that glucocorticoids reduce the ability of neutrophils to respond to infections by downregulating TLR2 via GILZ, thereby reducing critical functions.
糖皮质激素是目前最强大的抗炎和免疫抑制药物，尽管它们有不良反应。糖皮质激素诱导亮氨酸拉链（GILZ）是一种糖皮质激素诱导的基因，与糖皮质激素具有许多抗炎特性。尽管糖皮质激素对中性粒细胞的免疫抑制作用仍知之甚少，但我们之前证明 GILZ 可抑制糖皮质激素治疗下的中性粒细胞活化。在这里，我们试图探讨合成糖皮质激素地塞米松（DEX）对中性粒细胞中 Toll 样受体 2（TLR2）的调节及其与 GILZ 的关联。从野生型和 GILZ 敲除（KO）小鼠中分离外周血中性粒细胞。发现糖皮质激素体内给药可下调野生型中性粒细胞中的 TLR2，但不能下调 GILZ-KO 中性粒细胞中的 TLR2，表明 GILZ 参与了 TLR2 的下调。因此，DEX 处理可降低野生型中性粒细胞中 TLR2 相关的抗真菌活性，但不能降低 GILZ-KO 中性粒细胞中的活性。此外，GILZ 不与 NF-κB 相互作用，但与 STAT5 结合，STAT5 是调节 TLR2 表达的关键因素。体外用 DEX 处理循环人中性粒细胞时，观察到 TLR2 表达、吞噬作用和杀伤活性的类似调节。这些结果表明，糖皮质激素通过 GILZ 下调 TLR2，从而降低中性粒细胞对感染的反应能力，从而降低关键功能。
