Freie Universität Berlin, Institute of Pharmacy (Pharmacology and Toxicology), Germany; University of Bonn, Pharmaceutical Institute, Section Pharmacology and Toxicology, Germany.
University of Bonn, Pharmaceutical Institute, Section Pharmacology and Toxicology, Germany.
Biochem Pharmacol. 2020 May;175:113864. doi: 10.1016/j.bcp.2020.113864. Epub 2020 Feb 20.
Interleukin (IL)-1 signaling leads to production of pro-inflammatory mediators and is regulated by receptor endocytosis. Lysosomotropic drugs have been linked to increased pro-inflammatory responses under sterile inflammatory conditions but the underlying mechanisms have not been fully elucidated. Here, we report that lysosomotropic drugs potentiate pro-inflammatory effects in response to IL-1β via a mechanism involving reactive oxygen species, p38 mitogen-activated protein kinase and reduced IL-1 receptor internalization. Chloroquine and hydroxychloroquine increased IL-1β-induced CXCL8 secretion in macrophages which was critically dependent on the lysosomotropic character and inhibition of macroautophagy but independent from the NLRP3 inflammasome. Co-stimulation with the autophagy inducer interferon gamma attenuated CXCL8 release. Other lysosomotropic drugs like bafilomycin A, fluoxetine and chlorpromazine but also the endocytosis inhibitor dynasore showed similar pro-inflammatory responses. Increased cell surface expression of IL-1 receptor suggests reduced receptor degradation in the presence of lysosomotropic drugs. Our findings provide new insights into a potentially crucial immunoregulatory mechanism in macrophages that may explain how lysosomotropic drugs drive sterile inflammation.
白细胞介素 (IL)-1 信号转导导致促炎介质的产生，并受受体内吞作用的调节。溶酶体靶向药物与无菌炎症条件下促炎反应的增加有关，但潜在的机制尚未完全阐明。在这里，我们报告溶酶体靶向药物通过涉及活性氧、p38 丝裂原活化蛋白激酶和减少 IL-1 受体内化的机制增强了对 IL-1β 的促炎作用。氯喹和羟氯喹增加了巨噬细胞中 IL-1β 诱导的 CXCL8 分泌，这严重依赖于溶酶体靶向特性和巨自噬的抑制，但与 NLRP3 炎性体无关。与自噬诱导剂干扰素 γ 共同刺激可减弱 CXCL8 的释放。其他溶酶体靶向药物，如巴弗洛霉素 A、氟西汀和氯丙嗪，以及内吞抑制剂 dynasore 也表现出类似的促炎反应。溶酶体靶向药物存在时，IL-1 受体的细胞表面表达增加表明受体降解减少。我们的发现为巨噬细胞中潜在的关键免疫调节机制提供了新的见解，这可能解释了溶酶体靶向药物如何引发无菌炎症。
