免疫抑制性受体LILRB2促进新型冠状病毒刺突蛋白介导的炎症过程

doi:10.3969/j.issn.1674-8115.2022.09.005

上海交通大学学报（医学版） ›› 2022, Vol. 42 ›› Issue (9): 1188-1196.doi: 10.3969/j.issn.1674-8115.2022.09.005

• 创新团队成果专栏 • 上一篇

免疫抑制性受体LILRB2促进新型冠状病毒刺突蛋白介导的炎症过程

杨文倩¹(), 陈迟琪¹(), 赵路¹, 曹力元¹, 夏一秋¹, 卢智刚²(), 郑俊克¹()

^1.上海交通大学医学院细胞分化与凋亡教育部重点实验室，上海 200025
^2.复旦大学生物医学研究院，上海 200032

收稿日期:2022-06-13 接受日期:2022-08-21 出版日期:2022-09-28 发布日期:2022-09-28
通讯作者: 卢智刚,郑俊克 E-mail:117710910043@sjtu.edu.cn;zhiganglu@fudan.edu.cn;zhengjunke@shsmu.edu.cn
作者简介:杨文倩（1994—），女，博士生；电子信箱：117710910043@sjtu.edu.cn
杨文倩（1994—），女，博士生；电子信箱：117710910043@sjtu.edu.cn
基金资助:
国家自然科学基金(81825001);上海市科学技术委员会科学基金(19XD1422100)

Immune inhibitory receptor LILRB2 enhances SARS-CoV-2 spike protein-mediated immune inflammation

YANG Wenqian¹(), CHEN Chiqi¹(), ZHAO Lu¹, CAO Liyuan¹, XIA Yiqiu¹, LU Zhigang²(), ZHENG Junke¹()

^1.Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
^2.Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China

Received:2022-06-13 Accepted:2022-08-21 Online:2022-09-28 Published:2022-09-28
Contact: LU Zhigang,ZHENG Junke E-mail:117710910043@sjtu.edu.cn;zhiganglu@fudan.edu.cn;zhengjunke@shsmu.edu.cn
Supported by:
National Natural Science Foundation of China(81825001);Scientific Project of Science and Technology Commission of Shanghai Municipality(19XD1422100)

摘要/Abstract

摘要：

目的·探究免疫抑制性受体白细胞免疫球蛋白样受体亚家族B成员2（leukocyte immunoglobulin-like receptor subfamily B member 2，LILRB2）在新型冠状（新冠）病毒感染所导致的免疫细胞炎症因子释放中的作用及机制，为新冠病毒肺炎治疗提供潜在靶点。方法·收集包含刺突蛋白胞外段（S-ECD）的细胞上清液，分别使用Western blotting及流式细胞术检测上清液中蛋白表达情况及活性；通过流式细胞术及免疫共沉淀技术检测该上清液中S-ECD与LILRB2的结合；用刺突蛋白处理人单核细胞系THP1或人外周血单个核细胞（peripheral blood mononuclear cell，PBMC），24 h后收集细胞，使用实时定量PCR技术检测相关炎症因子基因mRNA水平改变，同时使用酶联免疫吸附法检测细胞培养液中白细胞介素6（interleukin-6，IL-6）及IL-1β含量；将siLILRB2通过Lipofectamine 3000试剂转染至人外周血CD33⁺髓系细胞中，24 h后使用流式细胞术检测基因干扰效果；在对照组及LILRB2敲低的CD33⁺髓系细胞中加入刺突蛋白培养24 h，使用酶联免疫吸附试剂盒检测细胞培养液中IL-6的含量变化。结果·实验成功构建可分泌具有生物活性的新冠病毒S-ECD的293T细胞转染体系；免疫共沉淀实验显示刺突蛋白与LILRB2蛋白存在相互作用，且流式细胞术结果提示刺突蛋白胞外段能够与细胞表面的LILRB2结合；与对照组相比，经刺突蛋白处理24 h的THP1细胞中IL-6、IL-8、精氨酸酶（arginase 1）及IL-2基因表达水平均有明显上调（均P<0.05）；PBMC经刺突蛋白处理24 h后，IL-6、转化生长因子-β（transforming growth factor-β，TGF-β）、IL-8、IL-10及IL-1β的mRNA水平均显著上升（均P<0.05）；酶联免疫吸附实验结果显示，在PBMC培养液中加入刺突蛋白能够提高上清液中IL-6及IL-1β的浓度（均P<0.05）；使用S-ECD或刺突蛋白处理CD33⁺髓系细胞，IL-1β及IL-6含量随之升高（均P<0.05）；并且过表达LILRB2的THP1细胞经刺突蛋白刺激后展现了更强的IL-6分泌能力（P<0.05）；流式细胞术检测结果显示，2条siRNA均能敲低CD33⁺髓系细胞中的LILRB2，且siLILRB2-1敲除效果更好；LILRB2缺失后，刺突蛋白则不能促进CD33⁺髓系细胞的IL-6分泌。结论·新冠病毒刺突蛋白通过与细胞表面分子LILRB2结合，引起髓系细胞释放IL-6、IL-1β等炎症因子，导致患者出现细胞因子释放综合征。

关键词: 新型冠状病毒, 刺突蛋白, 白细胞免疫球蛋白样受体亚家族B成员2, 炎症因子, 髓系细胞

Abstract:

Objective ·To explore the possible roles of immune inhibitory receptor leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) in the immune inflammation after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and provide a potential therapeutic way for the coronavirus disease 2019 (COVID-19). Methods ·The supernatants containing the extracellular domain of spike protein (S-ECD) were collected, and the detection of the protein expression and activity in the conditional medium by Western blotting and flow cytometric analysis was followed by. The binding of S-ECD with LILRB2 was measured by co-immunoprecipitation and flow cytometric analysis. The mRNA expression levels of several inflammation genes in a human mononuclear cell line (THP1) or peripheral blood mononuclear cells (PBMC) were measured after spike protein stimulation for 24 h by quantitative RT-PCR. The protein levels of interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the conditional medium were examined by enzyme-linked immunosorbent assay (ELISA). The siLILRB2 was transferred into CD33⁺ myeloid cells purified from human peripheral blood with Lipofectamine 3000 reagents. The knockdown efficiency was detected 24 h after transfection by flow cytometric analysis. The difference in the protein levels of IL-6 between the control cells and LILRB2-knocked-down cells after spike protein treatment was evaluated by ELISA. Results ·The study established a transfection system with 293T cells by which the SARS-CoV-2 S-ECD could be secreted to supernatants with normal biological activities. The interaction and the binding of spike protein with LILRB2 were evaluated by a co-immunoprecipitation assay and flow cytometric analysis, respectively. The mRNA expression levels of IL-6, IL-8, arginase 1 and IL-2 in THP1 cells were significantly up-regulated 24 h after spike protein treatment compared to the control cells (all P<0.05). Consistently, the mRNA levels of IL-6, transforming growth factor-β(TGF-β), IL-8, IL-10 and IL-1β in PBMC were notably increased after spike protein stimulation (all P<0.05). In addition, spike protein could also induce the release of IL-6 and IL-1β in PBMC as measured by ELISA (all P<0.05). More importantly, spike protein was able to increase the secretion of IL-1β and IL-6 by CD33⁺ myeloid cells 24 h after treatment (both P<0.05). LILRB2-overexpressing THP1 cells produced more IL-6 24 h after treatment with spike protein than the control cells (P<0.05). Two siRNAs could efficiently down-regulate the expression of LILRB2 in CD33⁺ cells as evaluated by flow cytometric analysis. Consistently, spike protein had no effect on the IL-6 secretion to supernatant from LILRB2-knockdown CD33⁺ myeloid cells. Conclusion ·SARS-CoV-2 can induce cytokine release syndrome by inflammatory factors, such as IL-6 and IL-1β, released by myeloid cells through spike protein binding to LILRB2.

Key words: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spike protein, leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), inflammatory cytokine, myeloid cell

中图分类号:

R363.1

杨文倩, 陈迟琪, 赵路, 曹力元, 夏一秋, 卢智刚, 郑俊克. 免疫抑制性受体LILRB2促进新型冠状病毒刺突蛋白介导的炎症过程[J]. 上海交通大学学报（医学版）, 2022, 42(9): 1188-1196.

YANG Wenqian, CHEN Chiqi, ZHAO Lu, CAO Liyuan, XIA Yiqiu, LU Zhigang, ZHENG Junke. Immune inhibitory receptor LILRB2 enhances SARS-CoV-2 spike protein-mediated immune inflammation[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(9): 1188-1196.

图/表 4

表1 qRT-PCR引物序列

Tab 1 Primer sequences for qRT-PCR

Gene （human）	Forward sequence （5'→3'）	Reverse sequence （5'→3'）
IL-6	ACTCACCTCTTCAGAACGAATTG	CCATCTTTGGAAGGTTCAGGTTG
IL-8	ACTGAGAGTGATTGAGAGTGGAC	AACCCTCTGCACCCAGTTTTC
IL-2	TCCTGTCTTGCATTGCACTAAG	CATCCTGGTGAGTTTGGGATTC
IL-10	GACTTTAAGGGTTACCTGGGTTG	TCACATGCGCCTTGATGTCTG
IL-1β	ATGATGGCTTATTACAGTGGCAA	GTCGGAGATTCGTAGCTGGA
ARG-1^①	TGGACAGACTAGGAATTGGCA	CCAGTCCGTCAACATCAAAACT
TGF-β	GGCCAGATCCTGTCCAAGC	GTGGGTTTCCACCATTAGCAC
actin	AGAGCTACGAGCTGCCTGAC	AGCACTGTGTTGGCGTACAG

图1 LILRB2能够与新冠病毒S-ECD相互作用Note： A. The protein level of S-ECD in the conditional medium from transfected 293T cells was detected by Western blotting. B. ACE2-expressing 293T cells were incubated with S-ECD-hFc or hFc, followed by the analysis for the binding by flow cytometry. C. LILRB2-expressing 293T cells were incubated with S-ECD-hFc or hFc, followed by the analysis for the binding by flow cytometry. Binding of S-ECD-hFc or hFc control to LILRB2 were shown (mean fluorescent intensity of APC fluorescence). D. The interaction of S-ECD with LILRB2 was determined by a co-immunoprecipitation assay. The arrows indicate the positions of the S-ECD protein. Ctrl—control; IP—immunoprecipitation; IB—immunoblotting; EV—empty vector.

Fig 1 LILRB2 interacting with S-ECD of SARS-CoV-2

图2 刺突蛋白促进THP1细胞及PBMC炎症因子的表达和分泌Note： A. The mRNA expression levels of IL-6, IL-8, ARG1 and IL-2 were up-regulated in THP1 cells 24 h after spike protein treatment. B. The mRNA expression levels of IL-6, TGF-β, IL-8, IL-10, and IL-1β were up-regulated in PBMC 24 h after spike protein treatment. C/D. The protein levels of IL-6 and IL-1β in the supernatant were measured by ELISA. IL-6 (C) and IL-1β (D) protein levels in the conditional medium from PBMC were significantly increased after spike protein stimulation. ①P=0.009, ②P=0.002, ③P=0.037, ④P=0.006, ⑤P=0.023, ⑥P=0.000, ⑦P=0.002, ⑧P=0.001, ⑨P=0.030, ⑩P=0.009, ?P=0.004.

Fig 2 Spike protein promoting the expression and release of inflammatory cytokines in THP1 cells and PBMC

图3 LILRB2 敲低能够抑制刺突蛋白导致的髓系细胞IL-6分泌的增加Note： A/B. The protein levels of IL-1β and IL-6 were determined by ELISA. The concentrations of IL-6 (A) and IL-1β (B) in culture medium from CD33+ myeloid cells were increased 24 h after treatment with S-ECD-hFc. C. IL-6 protein level was increased in CD33+ myeloid cells 24 h after spike protein stimulation. D. The overexpression of LILRB2 in THP1 cells promoted IL-6 release after spike protein stimulation. E. The knockdown efficiency of LILRB2 by RNA interference in CD33+ myeloid cells was determined by flow cytometric analysis. F. IL-6 protein level was decreased in LILRB2-knockdwon CD33+ myeloid cells 24 h after treatment with spike protein. G. The protein levels of total-SHP2 and p-SHP2 were determined in LILRB2-overexpressing THP1 cells after treatment with spike protein by Western blotting. ①P=0.022, ②P=0.020,③P=0.008,④P=0.045, ⑤P=0.021,⑥P=0.007,⑦P=0.003, ⑧P=0.059.

Fig 3 LILRB2 knockdown in myeloid cells suppressing spike protein induced IL-6 secretion

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免疫抑制性受体LILRB2促进新型冠状病毒刺突蛋白介导的炎症过程

Immune inhibitory receptor LILRB2 enhances SARS-CoV-2 spike protein-mediated immune inflammation

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