Gong Ying, Jin Lingyue, Duan Lina, Xiao Jie, Li Yao, Wang HongXia, Wang Haifang, Lin Wanying, Zhang Yi, Gan Xiufeng, Pang Shuyin, Qiu Yurong, Lai Weinan, Zheng Lei, Li Haixia
Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
Guangdong Provincial Clinical Research Center for Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
J Extracell Vesicles. 2025 Jul;14(7):e70134. doi: 10.1002/jev2.70134.
Systemic lupus erythematosus (SLE) has been linked to gut microbiome dysbiosis, notably an overabundance of Streptococcus anginosus; however, the impact of this microbial imbalance on disease pathogenesis remains unclear. Here, we investigated the contribution of S. anginosus-derived extracellular vesicles (SA-EVs) to SLE progression, with an emphasis on lupus nephritis (LN). Fifty-four SLE patients and 43 healthy controls (HC) were recruited. The faecal, blood and serum samples from participants were collected. SLE disease activity (SLEDA) was evaluated by the SLEDA Index (SLEDAI). Stool S. anginosus abundance was quantified by quantitative PCR, NK cell activation by flow cytometry and serum proinflammatory cytokines profile by ELISA. Lupus-prone MRL/lpr mice were orally administered SA-EVs to evaluate in vivo inflammatory responses, renal NK cell activation and renal histopathological changes. S. anginosus levels were significantly elevated in SLE patients relative to HC, positively correlated with SLEDAI scores and NK cell cytotoxicity. In vitro, SA-EVs stimulation of patient NK cells significantly heightened proinflammatory mediator production (granzyme B, TNF-α), increased cytotoxicity and downregulated inhibitory receptors (TIM-3, NKG2A, TIGIT) compared to control EVs from S. Salivarius (SS-EVs). Mechanistically, lipoteichoic acid (LTA) within SA-EVs engaged Toll-like receptor 2 (TLR2) on NK cells, activating MyD88/NF-κB signalling pathway. In MRL/lpr mice, SA-EVs treatment increased renal immune complex deposition, upregulated renal NK cell activation markers (NKp44, NKp46), and exacerbated LN pathology with greater immune cell infiltration and inflammatory cytokine levels. Furthermore, NK cell depletion with anti-NK1.1 antibodies significantly prolonged survival in SA-EVs administered mice. Thus, SA-EVs exacerbate SLE by hyperactivating NK cells via the TLR2-MyD88-NF-κB pathway, leading to amplified systemic inflammation and aggravated LN. These findings underscore the potential of targeting SA-EVs for therapeutic intervention in SLE.
系统性红斑狼疮（SLE）与肠道微生物群失调有关，尤其是咽峡炎链球菌过度增殖；然而，这种微生物失衡对疾病发病机制的影响仍不清楚。在此，我们研究了咽峡炎链球菌衍生的细胞外囊泡（SA-EVs）对SLE进展的作用，重点关注狼疮性肾炎（LN）。招募了54例SLE患者和43名健康对照（HC）。收集参与者的粪便、血液和血清样本。通过SLE疾病活动指数（SLEDAI）评估SLE疾病活动度（SLEDA）。通过定量PCR定量粪便中咽峡炎链球菌丰度，通过流式细胞术检测NK细胞活化情况，通过ELISA检测血清促炎细胞因子谱。对易患狼疮的MRL/lpr小鼠口服给予SA-EVs，以评估体内炎症反应、肾脏NK细胞活化和肾脏组织病理学变化。与HC相比，SLE患者的咽峡炎链球菌水平显著升高，与SLEDAI评分和NK细胞细胞毒性呈正相关。在体外，与来自唾液链球菌的对照囊泡（SS-EVs）相比，SA-EVs刺激患者NK细胞显著提高促炎介质产生（颗粒酶B、TNF-α），增加细胞毒性并下调抑制性受体（TIM-3、NKG2A、TIGIT）。从机制上讲，SA-EVs内的脂磷壁酸（LTA）与NK细胞上的Toll样受体2（TLR2）结合，激活MyD88/NF-κB信号通路。在MRL/lpr小鼠中，SA-EVs治疗增加肾脏免疫复合物沉积，上调肾脏NK细胞活化标志物（NKp44、NKp46），并加重LN病理，伴有更多免疫细胞浸润和炎症细胞因子水平升高。此外，用抗NK1.1抗体清除NK细胞可显著延长给予SA-EVs小鼠的生存期。因此，SA-EVs通过TLR2-MyD88-NF-κB途径过度激活NK细胞，加剧SLE，导致全身炎症放大和LN加重。这些发现强调了靶向SA-EVs进行SLE治疗干预的潜力。
Sheng Li Xue Bao. 2025-6-25
Clin Rev Allergy Immunol. 2025-4-11
Clin Rev Allergy Immunol. 2025-1-17
Nat Immunol. 2024-8
Lancet. 2024-5-25
JAMA. 2024-5-7
J Extracell Vesicles. 2024-4
Nature. 2024-2
Zotero 插件