Immune infiltration mechanism of differential expression genes in rheumatoid arthritis and potential therapeutic prediction of Chinese herbs

doi:10.3969/j.issn.2095-4344.3797

Abstract

Abstract: BACKGROUND: The pathogenesis of rheumatoid arthritis is not completely clear. Immune imbalance is an important link in the pathogenesis of rheumatoid arthritis, and research on the related regulatory mechanism of immune infiltration in rheumatoid arthritis is less reported.
OBJECTIVE: to analyze the pathway enrichment and immune infiltration of rheumatoid arthritis gene probe chip data by using GEO gene chip database, and to predict the biological process of immune regulation in rheumatoid arthritis, thereby providing a theoretical basis for understanding the immune mechanism of rheumatoid arthritis and the intervention of traditional Chinese medicine in immune regulation.
METHODS: The GEO gene chip database was searched for synovial tissue-related gene probes of rheumatoid arthritis, and the normal synovial tissue was used as control. Protein-protein interaction network of different genes was analyzed using STRING database, to screen out core target genes. The gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) gene pathway enrichment analysis of differential genes related to rheumatoid arthritis was performed using R language and related installation package program. The content and proportion of 22 kinds of immune cells in rheumatoid arthritis group and control group were analyzed by CIBERSORT deconvolution method. Significantly enriched immune-related biological processes and core target genes were predicted using the COREMINE database.
RESULTS AND CONCLUSION: Rheumatoid arthritis-associated protein networks interacted with core target genes involving CDC20, GNB3, QSOX1 and 12 genes associated with chemokines. GO enrichment analysis showed that up-regulated genes were more closely related to immune inflammation. KEGG enrichment analysis showed that immune regulation of rheumatoid arthritis was closely related to chemokine signaling pathway, interleukin-17 related pathway and nuclear factor-κB pathway. Analysis of the infiltration matrix of immune cells showed that the proportion of plasma cells, memory B cells and M0 macrophages in rheumatoid arthritis group increased significantly, while the number of M2 macrophages and resting mast cells was significantly reduced in the synovial tissues of rheumatoid arthritis. Correlation analysis between immune cells indicated that the unactivated natural killer cells of rheumatoid arthritis were positively correlated with neutrophils, and the activated CD4 memory T cells were strongly negatively correlated with activated natural killer cells. Through COREMINE prediction, mulberry leaf, fish brain stone and yam were found to be most closely related to the immune pathways and core target genes associated with rheumatoid arthritis. The mechanism may be related to interference with leukocyte and T cell migration by acting on the target genes, CCR5, CXCL10, CXCR3, and CXCL13. Overall, M2 macrophages and resting mast cells are closely related to rheumatoid arthritis. Rheumatoid arthritis-related differential genes are involved in immune-related biological processes, including neutrophil activation, leukocyte chemotaxis and T cell migration, as well as correlated with chemokine signaling pathways, interleukin-17-related pathway, and nuclear factor-κB-related pathway. Mulberry leaves, fish-brain stones, and yam may be the potential molecular drug sources.

Key words: rheumatoid arthritis, immune infiltration, GEO gene chip database, bioinformatics, CIBERSORT deconvolution, traditional Chinese medicine prediction, signaling pathway, mechanism research

CLC Number:

Shen Fu, Kuang Gaoyan, Yang Zhuo, Wen Meng, Zhu Kaimin, Yu Guizhi, Xu Wuji, Deng Bo . Immune infiltration mechanism of differential expression genes in rheumatoid arthritis and potential therapeutic prediction of Chinese herbs[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(14): 2183-2191.

Figures/Tables 9

References

[1] FALCONER J, MURPHY AN, YOUNG SP, et al. Review: synovial cell metabolism and chronic inflammation in rheumatoid arthritis. Arthritis Rheumatol. 2018; 70(7):984-999.
[2] MCINNES IB, SCHETT G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 2017;389(10086):2328-2337.
[3] SHI YQ, QI WF, KONG CY. Drug screening and identification of key candidate genes and pathways of rheumatoid arthritis. Mol Med Rep. 2020;22(2):986-996.
[4] AREND WP, FIRESTEIN GS. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat Rev Rheumatol. 2012;8(10):573-586.
[5] COUTANT F, MIOSSEC P. Evolving concepts of the pathogenesis of rheumatoid arthritis with focus on the early and late stages. Curr Opin Rheumatol. 2020; 32(1):57-63.
[6] FANG Q, ZHOU C, NANDAKUMAR KS. Molecular and cellular pathways contributing to joint damage in rheumatoid arthritis. Mediators Inflamm. 2020; 2020:3830212.
[7] ORR C, VIEIRA-SOUSA E, BOYLE DL, et al. Corrigendum: synovial tissue research: a state-of-the-art review. Nat Rev Rheumatol. 2017;14(1):60.
[8] FANG Q, OU J, NANDAKUMAR KS. Autoantibodies as diagnostic markers and mediator of joint inflammation in arthritis. Mediators Inflamm. 2019;2019: 6363086.
[9] YANG X, CHANG Y, WEI W. Emerging role of targeting macrophages in rheumatoid arthritis: Focus on polarization, metabolism and apoptosis. Cell Prolif. 2020;53(7): e12854.
[10] ROBERTS CA, DICKINSON AK, TAAMS LS. The Interplay Between Monocytes/Macrophages and CD4(+) T Cell Subsets in Rheumatoid Arthritis. Front Immunol 2015;6:571.
[11] SMOLEN JS, LANDEWÉ R, BIJLSMA J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-699.
[12] 逯卓卉,韦登明,张伊,等.组织工程方法修复类风湿性关节炎软骨缺损的研究进展[J].北京生物医学工程,2013,32(3):315-319.
[13] CHATZIDIONYSIOU K, SFIKAKIS PP. Low rates of remission with methotrexate monotherapy in rheumatoid arthritis: review of randomised controlled trials could point towards a paradigm shift. RMD Open. 2019;5(2):e000993.
[14] XING Q, FU L, YU Z, et al. Efficacy and safety of integrated traditional chinese medicine and western medicine on the treatment of rheumatoid arthritis: a meta-analysis. Evid Based Complement Alternat Med. 2020;2020:4348709.
[15] 陈坤威,童亚林,姚咏明.组织工程支架材料对固有免疫反应的影响及调控效应[J]. 解放军医学杂志,2018,43(8):698-703.
[16] GUO X, JI J, FENG Z, et al. A network pharmacology approach to explore the potential targets underlying the effect of sinomenine on rheumatoid arthritis. Int Immunopharmacol. 2020;80:106201.
[17] 池里群,周彬,高文远,等.治疗类风湿性关节炎常用药物的研究进展[J].中国中药杂志,2014,39(15):2851-2858.
[18] 王亚黎,刘健,叶文芳,等.中医药对类风湿关节炎患者免疫球蛋白影响的研究进展[J].风湿病与关节炎,2014,3(4):62-65.
[19] MOROZ LA, TALAKO ТМ, POTAPNEV MP, et al. Dichotomy of Local Th1- and Systemic Th2/Th3-Dependent Types of Immune Response in Rheumatoid Arthritis. Bull Exp Biol Med. 2019;167(1):69-73.
[20] KOMATSU N, TAKAYANAGI H. Immune-bone interplay in the structural damage in rheumatoid arthritis. Clin Exp Immunol. 2018;194(1):1-8.
[21] ALI HR, CHLON L, PHAROAH PD, et al. Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLoS Med. 2016;13(12):e1002194.
[22] XIONG Y, WANG K, ZHOU H, et al. Profiles of immune infiltration in colorectal cancer and their clinical significant: a gene expression-based study. Cancer Med. 2018;7(9):4496-4508.
[23] NEWMAN AM, LIU CL, GREEN MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453-457.
[24] LU G, CHEN L, WU S, et al. Comprehensive Analysis of Tumor-Infiltrating Immune Cells and Relevant Therapeutic Strategy in Esophageal Cancer. Dis Markers. 2020; 2020:8974793.
[25] 古龙,周牮,彭建华,等.颅内动脉瘤的相关信号通路基因集富集及免疫浸润分析[J].中国实验方剂学杂志,2020,26(7):178-185.
[26] LAN YY, WANG YQ, LIU Y. CCR5 silencing reduces inflammatory response, inhibits viability, and promotes apoptosis of synovial cells in rat models of rheumatoid arthritis through the MAPK signaling pathway. J Cell Physiol. 2019;234(10): 18748-18762.
[27] GUO Q, ZHENG K, FAN D, et al. Wu-Tou Decoction in rheumatoid arthritis: integrating network pharmacology and in vivo pharmacological evaluation. Front Pharmacol. 2017;8:230.
[28] LEE JH, KIM B, JIN WJ, et al. Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis. Arthritis Res Ther. 2017;19(1):163.
[29] ARMAS-GONZÁLEZ E, DOMÍNGUEZ-LUIS MJ, DÍAZ-MARTÍN A, et al. Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis. Arthritis Res Ther. 2018;20(1):114.
[30] PANDYA JM, LUNDELL AC, ANDERSSON K, et al. Blood chemokine profile in untreated early rheumatoid arthritis: CXCL10 as a disease activity marker. Arthritis Res Ther. 2017;19(1):20.
[31] MIYABE Y, LIAN J, MIYABE C, et al. Chemokines in rheumatic diseases: pathogenic role and therapeutic implications. Nat Rev Rheumatol. 2019;15(12):731-746.
[32] TSUJIMURA S, ADACHI T, SAITO K, et al. Relevance of P-glycoprotein on CXCR4+ B cells to organ manifestation in highly active rheumatoid arthritis. Mod Rheumatol. 2018;28(2):276-286.
[33] COSTANTINO AB, ACOSTA C, ONETTI L, et al. Follicular helper T cells in peripheral blood of patients with rheumatoid arthritis. Reumatol Clin. 2017;13(6):338-343.
[34] ZHOU LF, ZENG W, SUN LC, et al. IKKε aggravates inflammatory response via activation of NF-κB in rheumatoid arthritis. Eur Rev Med Pharmacol Sci. 2018; 22(7):2126-2133.
[35] LIU YR, YAN X, YU HX, et al. NLRC5 promotes cell proliferation via regulating the NF-κB signaling pathway in Rheumatoid arthritis. Mol Immunol. 2017;91:24-34.
[36] ONISHI RM, PARK SJ, HANEL W, et al. SEF/IL-17R (SEFIR) is not enough: an extended SEFIR domain is required for IL-17RA-mediated signal transduction. J Biol Chem. 2010;285(43):32751-32759.
[37] 郭江燕,高梓珊,姜姝姝,等.IL-17和NF-κB通路与类风湿性关节炎的相关性研究[J].长春中医药大学学报,2015,31(1):192-194.
[38] 董甜甜,王金龄,李世刚,等.肥大细胞在小鼠佐剂性关节炎疼痛中的作用及其机制研究[J].中国病理生理杂志,2020,36(4):693-699.
[39] OKAMURA Y, MISHIMA S, KASHIWAKURA JI, et al. The dual regulation of substance P-mediated inflammation via human synovial mast cells in rheumatoid arthritis. Allergol Int. 2017;66S:S9-9S20.
[40] KUNG CC, DAI SP, CHIANG H, et al. Temporal expression patterns of distinct cytokines and M1/M2 macrophage polarization regulate rheumatoid arthritis progression. Mol Biol Rep. 2020;47(5):3423-3437.
[41] 阮静瑶,陈必成,张喜乐,等.巨噬细胞M1/M2极化的信号通路研究进展[J].免疫学杂志,2015,31(10):911-917.
[42] 王艳霞.类风湿性关节炎滑膜淋巴细胞CD3、CD4、CD8的表达及意义[D].天津:天津医科大学,2012:1-60.
[43] 田杰祥,陶永明,王钢,等.中医药治疗类风湿关节炎滑膜炎的机理研究进展[J].中医药学报,2019,47(3):122-124.
[44] 张佳琪.基于焦树德教授治疗类风湿关节炎辨证分型的用药规律探讨[J].风湿病与关节炎,2017,6(12):33-37.
[45] 卜祥伟,张红红,张建萍,等.基于数据挖掘探讨孟凤仙教授治疗类风湿关节炎用药规律[J].中华中医药学刊,2018,36(7):1573-1576.
[46] 蔡辉,陆乐,赵智明.“以毒攻毒”在类风湿关节炎治疗中的运用[J].中医学报,2015,30(11):1664-1666.
[47] NIU X, HE Z, LI W, et al. Immunomodulatory Activity of the Glycoprotein Isolated from the Chinese Yam (Dioscorea opposita Thunb). Phytother Res. 2017;31(10): 1557-1563.
[48] JEONG JW, LEE HH, LEE KW, et al. Mori folium inhibits interleukin-1β-induced expression of matrix metalloproteinases and inflammatory mediators by suppressing the activation of NF-κB and p38 MAPK in SW1353 human chondrocytes. Int J Mol Med. 2016;37(2):452-460.
[49] 侯瑞宏,廖森泰,刘凡,等.桑叶多糖对小鼠免疫调节作用的影响[J].食品科学,2011,32(13):280-283.
[50] 赵婷,高昂,巩江,等.鱼脑石药学研究概况[J].辽宁中医药大学学报,2011, 13(9):82-84.
[51] 匡红,解葵,孙晨,等.512例类风湿关节炎患者血清5种微量元素含量分析[J].国际检验医学杂志,2013,34(10):1214-1215,1218.
[52] 吴文英,张如峰,马凤英,等.不同药物治疗对类风湿关节炎患者血清铜、硒及锌水平的影响[J].中国老年学杂志,2015,35(6):1555-1556.