肿瘤坏死因子-α在新型冠状病毒感染合并肾损伤中的作用

doi:10.3969/j.issn.1674-8115.2025.01.001

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (1): 1-10.doi: 10.3969/j.issn.1674-8115.2025.01.001

• 论著 · 基础研究 • 下一篇

肿瘤坏死因子-α在新型冠状病毒感染合并肾损伤中的作用

PANDIT Roshan¹(), 卢君瑶²(), 何立珩¹, 包玉洁², 季萍¹, 陈颖盈¹, 许洁²^,³(), 王颖¹^,³()

^1.上海交通大学基础医学院免疫学与微生物学系，上海市免疫学研究所，上海 200025
^2.上海交通大学医学院附属第九人民医院感染科，上海 201999
^3.上海交通大学医学院上海市病毒研究院，上海 200025

接受日期:2024-08-16 出版日期:2025-01-28 发布日期:2025-01-28
通讯作者: 王　颖，教授，博士；电子信箱：ywangssmu@shsmu.edu.cn
许　洁，主任医师，硕士；电子信箱：dr.xu@aliyun.com。
作者简介:PANDIT Roshan（1993—），男，尼泊尔，硕士生；电子信箱：p_roshan@sjtu.edu.cn
卢君瑶（1986—），女，硕士生；电子信箱：lu_junyao@163.com。
第一联系人：*为共同第一作者。
基金资助:
国家重点研发计划(2021YFC2301502);上海交通大学“交大之星”计划医工交叉研究基金(YG2023ZD02);市级医院临床管理优化项目(SHDC22021207)

Role of tumor necrosis factor-α in coronavirus disease 2019-associated kidney injury

PANDIT Roshan¹(), LU Junyao²(), HE Liheng¹, BAO Yujie², JI Ping¹, CHEN Yingying¹, XU Jie²^,³(), WANG Ying¹^,³()

^1.Shanghai Institute of Immunology, Department of Microbiology and Immunology, Shanghai Jiao Tong University College of Basic Medical Sciences Shanghai 200025, China
^2.Department of Infectious Diseases, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China
^3.Shanghai Institute of Virology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Accepted:2024-08-16 Online:2025-01-28 Published:2025-01-28
Contact: WANG Ying, E-mail: ywangssmu@shsmu.edu.cn
XU Jie, E-mail: dr.xu@aliyun.com.
Supported by:
National Key Research and Development Program of China(2021YFC2301502);the Fundamental Research Funds for the Central Universities(YG2023ZD02);Municipal Hospital Clinical Management Optimization Project(SHDC22021207)

摘要/Abstract

摘要：

目的·筛选新型冠状病毒感染（coronavirus disease-2019，COVID-19）患者合并肾损伤（kidney injury，KI）的相关标志物，探讨新型冠状病毒蛋白通过影响肾脏细胞与巨噬细胞间相互作用参与肾损伤的相关机制。方法·回顾性分析2022年12月—2023年2月上海交通大学医学院第九人民医院收治的COVID-19合并KI患者的临床特征，采用酶联免疫吸附试验（enzyme linked immunosorbent assay，ELISA）检测血清中的炎症因子和趋化因子水平。体外用严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus-2，SARS-CoV-2）重组刺突蛋白S1亚基刺激人巨噬细胞系THP-1后，收集细胞和培养上清，通过实时荧光定量PCR（quantitative real-time PCR，qRT-PCR）和ELISA检测炎症因子和趋化因子的水平。利用S1蛋白刺激THP-1的细胞培养上清制备条件培养基，体外刺激人肾上皮细胞系HK-2，并检测HK-2细胞分泌细胞因子的能力。采用抗体阻断实验分析条件培养基对HK-2细胞产生细胞因子的影响。结果·在39例COVID-19患者中，有8例（20.50%）血清肌酐水平高于正常参考范围，提示这些患者可能合并KI。ELISA结果显示COVID-19合并KI组患者外周肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）水平［（18.33±8.20）pg/mL］显著高于未合并KI组［（11.88±6.50）pg/mL］（P=0.015）。体外实验结果显示S1蛋白可以刺激THP-1胞内TNF-α、白细胞介素-1β（interleukin-1β，IL-1β）和C-X-C基序趋化因子配体10（chemokine C-X-C motif ligand 10，CXCL10）基因转录水平上升，同时刺激THP-1高表达TNF-α、IL-1β和CXCL10（P<0.001）。进一步研究发现，利用S1蛋白刺激THP-1的细胞培养上清制备的条件培养基能促进HK-2细胞表达TNF-α（P=0.005）。而采用抗TNF-α抗体（英夫利昔单抗，infliximab）阻断条件培养基中的TNF-α后，HK-2细胞表达TNF-α的水平显著降低（P<0.001）。结论·TNF-α在COVID-19合并KI患者中明显增高，提示TNF-α是COVID-19合并KI的重要炎症因子。细胞学实验证实新冠病毒S1蛋白可以诱导巨噬细胞分泌TNF-α，进而促进肾脏细胞炎症水平的增加，可能是COVID-19合并KI发生的主要原因。因此，靶向TNF-α有望成为降低COVID-19合并KI发生率的潜在新策略。

关键词: 肿瘤坏死因子-α, 新型冠状病毒感染, 肾损伤, 炎症反应, 干预靶点

Abstract:

Objective ·To identify relevant biomarkers for patients with coronavirus disease 2019-associated kidney injury (COVID-19-associated KI) and explore the mechanisms underlying the involvement of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) proteins in infection-related KI by affecting the interactions between renal cells and macrophages. Methods ·A retrospective analysis was conducted on the clinical characteristics of COVID-19 patients with KI treated in Shanghai Ninth, People′s, hospital from December 2022 to February 2023. Serum levels of inflammatory factors and chemokines were measured by using enzyme- linked immunosorbent assay (ELISA). In vitro, human macrophage cell line THP-1 cells were stimulated with recombinant S1 subunit protein derived from SARS-CoV-2 spike protein. The cells and culture supernatants were collected to detect the levels of inflammatory factors and chemokines by using quantitative real-time PCR (qRT-PCR) and ELISA. Conditioned medium was prepared from the cell culture supernatants of S1-stimulated THP-1 cells and used to stimulate human renal epithelial cells (HK-2) in vitro to assess cytokine secretion. Antibody blocking experiments were performed to analyze the effects of the conditioned medium on the production of cytokines in HK-2 cells. Results ·Among 39 patients with COVID-19, 8 (20.50%) had creatinine levels above the reference interval, which indicated the occurrence of KI. The levels of peripheral tumor necrosis factor-α (TNF-α) in the COVID-19 patient with KI group [(18.33±8.20) pg/mL] were significantly higher than those in the non-KI group [(11.88±6.50) pg/mL] (P=0.015). In vitro assay has shown that S1-spike protein stimulation promoted the level of gene transcription and production of TNF-α, interleukin-1β (IL-1β) and chemokine C-X-C motif ligand 10 (CXCL10) in THP-1 macrophage cells (P<0.001). Furthermore, the conditioned medium from S1-stimulated THP-1 cells promoted the secretion of TNF-α, IL-1β and CXCL10 by HK-2 cells (P=0.005). When anti-TNF-α antibody (Infliximab) was used to block TNF-α in the culture supernatants from S1-stimulated THP-1 cells, the secretion level of TNF-α by HK-2 cells decreased dramatically (P<0.001). Conclusion ·TNF-α levels increase significantly in COVID-19 patients with KI, implying the significance of TNF-α in the occurrence of COVID-19-associated KI. In vitro experiments confirm that the S1 protein induces TNF-α secretion from THP-1 cells, leading to increased inflammatory responses in renal cells, which may contribute to the development of COVID-19-associated KI. Therefore, targeting TNF-α may become an alternative strategy to reduce the occurrence of COVID-19-associated KI.

Key words: tumor necrosis factor-α, coronavirus disease 2019, kidney injury, inflammatory responses, therapeutic target

中图分类号:

R392.9

PANDIT Roshan, 卢君瑶, 何立珩, 包玉洁, 季萍, 陈颖盈, 许洁, 王颖. 肿瘤坏死因子-α在新型冠状病毒感染合并肾损伤中的作用[J]. 上海交通大学学报（医学版）, 2025, 45(1): 1-10.

PANDIT Roshan, LU Junyao, HE Liheng, BAO Yujie, JI Ping, CHEN Yingying, XU Jie, WANG Ying. Role of tumor necrosis factor-α in coronavirus disease 2019-associated kidney injury[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(1): 1-10.

图/表 8

表1 RT-PCR引物列表

Tab 1 Primer sequences used in RT-PCR

Target gene	Primer sequence (5′→3′)
IL1-β	Forward	ATGATGGCTTATTACAGTGGCAA
IL1-β	Reverse	GTCGGAGATTCGTAGCTGGA
TNF-α	Forward	CTCTTCTGCCTGCTGCACTTTG
TNF-α	Reverse	ATGGGCTACAGGCTTGTCACTC
CXCL10	Forward	GTGGCATTCAAGGAGTACCTC
CXCL10	Reverse	TGATGGCCTTCGATTCTGGATT
ACTB	Forward	CACCATTGGCAATGAGCGGTTC
ACTB	Reverse	AGGTCTTTGCGGATGTCCACGT
GAPDH	Forward	GGAGCGAGATCCCTCCAAAAT
GAPDH	Reverse	GGCTGTTGTCATACTTCTCATGG

图1 纳入本研究的患者人群特征

Fig 1 Characteristics of study samples

表2 COVID-19患者外周免疫细胞计数比较

Tab 2 Comparisons of peripheral immune cell numbers in COVID-19 patients

Item	Sex			Age group			Severity of pneumonia
Item	Male	Female	P value	≤60 years	>60 years	P value	Moderate	Severe	P value
WBC/(10⁹‧L^-1)	8.82±4.40	6.00±3.50	0.065	5.67±2.40	7.92±4.40	0.355	8.05±4.90	7.39±3.80	0.910
Neutrophil/%	77.06±14.70	77.92±10.90	0.808	77.57±6.40	77.39±13.80	0.437	72.86±16.10	80.88±9.30	0.100
Lymphocyte/%	15.21±13.50	15.32±9.50	0.830	15.57±4.80	15.22±12.60	0.355	19.96±15.50	11.67±6.80	0.060
Monocyte/%	6.74±3.60	5.82±2.30	0.368	6.40±4.20	6.36±3.10	0.721	6.19±2.80	6.50±3.50	0.734
Platelet/(10⁹‧L^-1)	211.95±100.80	199.66±90.50	0.775	282.75±139.40	197.78±87.50	0.585	202.25±54.00	210.57±119.30	1.000
CD3⁺ T cell/µL^-1	519.81±359.10	538.20±335.50	0.914	719.00±190.50	504.03±354.10	0.078	641.50±398.40	440.23±277.30	0.050
CD4⁺ T cell/µL^-1	255.63±143.80	318.60±237.90	0.722	386.75±127.70	268.36±190.60	0.156	309.62±152.40	259.47±211.10	0.137
CD8⁺ T cell/µL^-1	242.59±278.90	198.73±148.20	0.643	323.75±223.00	212.81±234.80	0.261	298.18±321.20	168.90±113.60	0.104
B cell/µL^-1	491.95±1 832.50	133.66±124.40	0.734	159.50±119.20	369.39±1 496.60	0.463	673.25±2 140.70	97.90±82.10	0.122
NK cell/µL^-1	154.63±118.50	145.60±224.80	0.205	123.00±113.40	154.36±173.30	0.642	155.93±124.90	147.19±196.00	0.263

表3 COVID-19患者外周肌酐水平和KI情况

Tab 3 Serum creatinine levels and kidney injury （KI） in COVID-19 patients

Group	Creatinine level in COVID-19 cohort/(µmol‧L^-1)			Status of KI
Group	Mean	Min. value	Max. value	KI/n (%)	Non-KI/n (%)	P value
Total	113.30±166.20	36.00	1 041.00	8 (20.50)	31 (79.50)
Gender						0.575
Male	140.73±211.40	36.00	1 041.00	5 (21.70)	18 (78.30)
Female	73.87±40.30	38.00	175.00	3 (18.70)	13 (81.30)
Age/year						0.171
≤60	249.20±442.80	38.00	1 041.00	1 (20.00)	4 (80.00)
61‒70	80.62±65.50	36.00	236.00	1 (12.50)	7 (87.50)
71‒80	87.28±73.90	40.00	336.00	1 (7.10)	13 (92.90)
>80	108.83±70.00	56.00	294.00	5 (41.70)	7 (58.30)

图2 COVID-19和COVID-19合并KI患者外周炎症因子水平Note： A. TNF-α level. B. IL-1β level. C. IL-6 level. D. IL-10 level. E. IL-8 level. F. IL-2R level. ①P=0.015, ②P=0.931, ③P=0.428, ④P=0.598, ⑤P=0.470, ⑥P=0.130.

Fig 2 Levels of peripheral inflammatory factors in non-KI (n=30) and KI (n=8) group

图3 SARS-CoV-2 S1重组蛋白体外刺激THP-1巨噬细胞产生炎症因子的水平Note： A‒C. Fold changes in TNF-α (A), IL1-β (B) and CXCL10 (C) mRNA levels in THP-1 cells upon stimulation with S1 spike protein at a concentration of 500 ng/mL for 4 h and 8 h. D‒F. Levels of TNF-α (D), IL-1β (E) and CXCL10 (F) in the supernatants of THP-1 cells stimulated with S1 spike protein (500 ng/mL) for 4 h and 8 h. ①P<0.001, ②P=0.001, ③P=0.008, compared with the control.

Fig 3 Levels of inflammatory factors induced by SARS-CoV-2 S1 recombinant protein in THP-1 macrophages in vitro

图4 经S1蛋白处理的THP-1细胞培养上清可诱导HK-2细胞的炎性特征Note： A. Diagram of the culture of HK-2 cells in conditioned medium for 24 h. Conditioned medium was obtained by stimulating THP-1 cells with S1 spike protein (500 ng/mL) for 4 h and 8 h. B. Fold changes in TNF-α mRNA levels in HK-2 cells cultured in conditioned medium compared to control HK-2 cells. C. Fold changes in CXCL10 mRNA levels in HK-2 cells cultured in conditioned medium compared to control HK-2 cells. ①P=0.005, compared with the control; ②P=0.225, compared with the HK-2+4 h sup; ③P=0.324, compared with the control; ④P=0.001, compared with the HK-2+4 h sup.

Fig 4 Inflammatory properties of HK-2 cells induced by the supernatants from S1 protein-treated THP-1 cells

图5 HK-2细胞的炎症反应依赖于S1蛋白处理THP-1细胞产生的TNF-αNote： A. Diagram of the culture of HK-2 cells in conditioned medium with the addition of Infliximab for 24 h. Conditioned medium was obtained by stimulating THP-1 cells with S1 protein (500 ng/mL) for 8h. B. Fold changes in TNF-α mRNA levels in HK-2 cells cultured in conditioned medium with the addition of Infliximab. C. TNF-α levels in THP-1 cells stimulated with S1 spike protein and in HK-2 cells cultured in conditioned medium with or without the addition of Infliximab. ①P<0.001.

Fig 5 Dependent of Inflammatory response in HK-2 cells on TNF-α produced by S1 protein-treated THP-1 cells

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肿瘤坏死因子-α在新型冠状病毒感染合并肾损伤中的作用

Role of tumor necrosis factor-α in coronavirus disease 2019-associated kidney injury

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