一个TLR7/9-IFNα-LDHB轴驱动重要的NET释放,并影响狼的抗菌防御
Eden G TenBarge1, Ashley D Wise1, Morgan L Hetzel1
1Department of Microbiology, University of Tennessee, Knoxville, TN, USA.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
系统性红斑狼 (SLE) 中性粒细胞由于乳酸感应受损而具有缺陷的细菌防御,导致有害的NETosis. 结合氧化和IFNAR阻塞可恢复SLE患者的NET功能和细菌清除.
科学领域:
- 免疫学 免疫学 免疫学
- 微生物学 微生物学
- 代谢途径 代谢途径
背景情况:
- 系统性红斑狼 (SLE) 患者对细菌感染的敏感性增加.
- 导致SLE抗菌防御受损的确切机制尚不完全理解.
- 中性细胞细胞外陷 (NETs) 对于对抗细菌病原体至关重要,但它们的功能可能在SLE中发生变化.
研究的目的:
- 阐明导致细菌感染易感性的SLE患者中性粒细胞的免疫代谢缺陷.
- 为了研究乳酸感应和SLE中性粒细胞中的NETosis的作用.
- 确定潜在的治疗策略,以恢复SLE中中性粒细胞的功能.
主要方法:
- 分析中性粒细胞功能,包括NETosis和乳酸感应,在健康个体和SLE患者.
- 调查托尔类受体 (TLR) 7/9信号传递对线粒体乳酸脱酶B (LDHB) 表达的影响.
- 在易患狼的小鼠模型和SLE患者衍生的中性粒细胞中评估联合基 (HCQ) 和干扰素α/β受体 (IFNAR) 阻塞.
- 对治疗干预措施的细菌清除反应的评估.
主要成果:
- 健康的中性粒细胞利用乳酸感应对线粒体依赖的自杀性NETosis对*黄金葡萄球菌*.
- SLE 中性粒细胞表现出缺陷的乳酸感应和自杀性NETosis,而是释放由I型干扰素 (IFN) 驱动的重要NETs.
- 在SLE中慢性TLR 7/9信号抑制LDHB,损害乳酸感应和NET平衡.
- 结合HCQ和IFNAR阻断恢复了小鼠和SLE患者中性粒细胞中的LDHB表达,NET平衡和细菌清除.
结论:
- 慢性自身免疫信号在SLE中通过免疫代谢乳酸感应的缺陷损害中性粒细胞的抗菌防御.
- 这种缺陷导致异常NETosis,有利于不那么有效的重要NET释放,而不是杀菌性自杀性NETosis.
- 准LDHB表达和IFN信号是一种有前途的治疗策略,可以改善SLE的抗菌防御.
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