Identification of key genes and pathways contributing to artery tertiary lymphoid organ development in advanced mouse atherosclerosis

Zhang,Xi; Liu,Fayuan; Bai,Peng; Dong,Nianguo; Chu,Chong

doi:10.3892/mmr.2019.9961

Identification of key genes and pathways contributing to artery tertiary lymphoid organ development in advanced mouse atherosclerosis

Authors:
- Xi Zhang
- Fayuan Liu
- Peng Bai
- Nianguo Dong
- Chong Chu
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Affiliations: Institute for Cardiovascular Prevention, Ludwig‑Maximilians University Munich, D‑80336 Munich, Germany, Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: February 15, 2019 https://doi.org/10.3892/mmr.2019.9961
Pages: 3071-3086
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Atherosclerosis is a leading cause of mortality worldwide. Artery tertiary lymphoid organ (ATLO) neogenesis is affected by abdominal aorta atherosclerosis, which may lead to an immune response. The present study obtained microarray data to investigate the gene expression differences underlying the potential pathogenesis of atherosclerosis and to elucidate the mechanisms underlying ATLO development. Microarray studies of the aorta, plaques, adventitia, blood, spleen, renal lymph nodes and ATLO were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in aorta clusters and ATLO clusters. Kyoto Encyclopedia of Genes and Genomes enrichment and Gene Ontology (GO) analyses were conducted to predict the biological functions of DEGs. The results demonstrated that interleukin 7 receptor (Il7r), C‑X‑C motif chemokine ligand (Cxcl)16, Cxcl13, Cxcl12, C‑C motif chemokine receptor 2, C‑C motif chemokine ligand (Ccl)8, Ccl5 and Ccl12 may function through pathways associated with ‘cytokine‑cytokine receptor interaction’ and ‘chemokine signaling pathway’ in ATLO. Gene expression alterations were validated by reverse transcription‑quantitative polymerase chain reaction. Il7r appeared to be the central gene involved in these events, and chemokines and/or chemokine receptors were visualized by GO enrichment. A protein‑protein interaction network was constructed, which suggested that Il7r had a core function in all clusters. Taken together, the results indicated that Il7r upregulation may serve an important role in ATLO development via ‘cytokine‑cytokine receptor interaction’ and ‘chemokine signaling pathway’. This may provide novel perspectives for understanding ATLO development and the regulation of the immune response in atherosclerosis.

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1	Brown AJ, Teng Z, Evans PC, Gillard JH, Samady H and Bennett MR: Role of biomechanical forces in the natural history of coronary atherosclerosis. Nat Rev Cardiol. 13:210–220. 2016. View Article : Google Scholar : PubMed/NCBI
2	Tabas I and Lichtman AH: Monocyte-macrophages and T cells in atherosclerosis. Immunity. 47:621–634. 2017. View Article : Google Scholar : PubMed/NCBI
3	Weber C and Noels H: Atherosclerosis: Current pathogenesis and therapeutic options. Nat Med. 17:1410–1422. 2011. View Article : Google Scholar : PubMed/NCBI
4	Huang X, Zou Y, Li L, Chen S, Hou J and Yu B: Relation of ABO blood groups to the plaque characteristic of coronary atherosclerosis. Biomed Res Int. 2017:26747262017. View Article : Google Scholar : PubMed/NCBI
5	Campbell KA, Lipinski MJ, Doran AC, Skaflen MD, Fuster V and McNamara CA: Lymphocytes and the adventitial immune response in atherosclerosis. Circ Res. 110:889–900. 2012. View Article : Google Scholar : PubMed/NCBI
6	Mohanta SK, Yin C, Peng L, Srikakulapu P, Bontha V, Hu D, Weih F, Weber C, Gerdes N and Habenicht AJ: Artery tertiary lymphoid organs contribute to innate and adaptive immune responses in advanced mouse atherosclerosis. Circ Res. 114:1772–1187. 2014. View Article : Google Scholar : PubMed/NCBI
7	Yin C, Mohanta SK, Srikakulapu P, Weber C and Habenicht AJ: Artery tertiary lymphoid organs: Powerhouses of atherosclerosis immunity. Front Immunol. 7:3872016. View Article : Google Scholar : PubMed/NCBI
8	Psaltis PJ, Puranik AS, Spoon DB, Chue CD, Hoffman SJ, Witt TA, Delacroix S, Kleppe LS, Mueske CS, Pan S, et al: Characterization of a resident population of adventitial macrophage progenitor cells in postnatal vasculature. Circ Res. 115:364–375. 2014. View Article : Google Scholar : PubMed/NCBI
9	He C, Medley SC, Hu T, Hinsdale ME, Lupu F, Virmani R and Olson LE: PDGFRbeta signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis. Nat Commun. 6:77702015. View Article : Google Scholar : PubMed/NCBI
10	Grabner R, Lotzer K, Dopping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B, Reardon CA, Getz GS, et al: Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE^−/− mice. J Exp Med. 206:233–248. 2009. View Article : Google Scholar : PubMed/NCBI
11	Srikakulapu P, Hu D, Yin C, Mohanta SK, Bontha SV, Peng L, Beer M, Weber C, McNamara CA, Grassia G, et al: Artery tertiary lymphoid organs control multilayered territorialized atherosclerosis B-Cell responses in aged ApoE^−/− mice. Arterioscler Thromb Vasc Biol. 36:1174–1185. 2016. View Article : Google Scholar : PubMed/NCBI
12	Hu D, Mohanta SK, Yin C, Peng L, Ma Z, Srikakulapu P, Grassia G, MacRitchie N, Dever G, Gordon P, et al: Artery tertiary lymphoid organs control aorta immunity and protect against atherosclerosis via vascular smooth muscle cell lymphotoxin β receptors. Immunity. 42:1100–1115. 2015. View Article : Google Scholar : PubMed/NCBI
13	Clement M, Guedj K, Andreata F, Morvan M, Bey L, Khallou-Laschet J, Gaston AT, Delbosc S, Alsac JM, Bruneval P, et al: Control of the T follicular helper-germinal center B-cell axis by CD8(+) regulatory T cells limits atherosclerosis and tertiary lymphoid organ development. Circulation. 131:560–570. 2015. View Article : Google Scholar : PubMed/NCBI
14	Gautier L, Cope L, Bolstad BM and Irizarry RA: Affy-analysis of affymetrix genechip data at the probe level. Bioinformatics. 20:307–315. 2004. View Article : Google Scholar : PubMed/NCBI
15	Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W and Smyth GK: limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43:e472015. View Article : Google Scholar : PubMed/NCBI
16	Walter W, Sanchez-Cabo F and Ricote M: GOplot: An R package for visually combining expression data with functional analysis. Bioinformatics. 31:2912–2914. 2015. View Article : Google Scholar : PubMed/NCBI
17	Gu W, Sun Y, Zheng X, Ma J, Hu XY, Gao T and Hu MJ: Identification of gastric cancer-related circular RNA through microarray analysis and bioinformatics analysis. Biomed Res Int. 2018:23816802018. View Article : Google Scholar : PubMed/NCBI
18	Altermann E and Klaenhammer TR: Pathway voyager: Pathway mapping using the Kyoto encyclopedia of genes and genomes (KEGG) database. BMC Genomics. 6:602005. View Article : Google Scholar : PubMed/NCBI
19	Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al: STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43:D447–D452. 2015. View Article : Google Scholar : PubMed/NCBI
20	Pang X, Zhao Y, Wang J, Zhou Q, Xu L, Kang, Liu AL and Du GH: The bioinformatic analysis of the dysregulated genes and MicroRNAs in entorhinal cortex, hippocampus, and blood for Alzheimer's Disease. Biomed Res Int. 2017:90845072017. View Article : Google Scholar : PubMed/NCBI
21	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Lotzer K, Dopping S, Connert S, Grabner R, Spanbroek R, Lemser B, Beer M, Hildner M, Hehlgans T, van der Wall M, et al: Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/lymphotoxin beta-receptor NF-kappaB signaling. Arterioscler Thromb Vasc Biol. 30:395–402. 2010. View Article : Google Scholar : PubMed/NCBI
24	Luther SA, Ansel KM and Cyster JG: Overlapping roles of CXCL13, interleukin 7 receptor alpha, and CCR7 ligands in lymph node development. J Exp Med. 197:1191–1198. 2003. View Article : Google Scholar : PubMed/NCBI
25	Ribeiro de Almeida C, Hendriks RW and Stadhouders R: Dynamic control of long-range genomic interactions at the immunoglobulin κ light-chain locus. Adv Immunol. 128:183–271. 2015. View Article : Google Scholar : PubMed/NCBI
26	Zhao L, Moos MP, Grabner R, Pedrono F, Fan J, Kaiser B, John N, Schmidt S, Spanbroek R, Lötzer K, et al: The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med. 10:966–973. 2004. View Article : Google Scholar : PubMed/NCBI
27	Schulz O, Hammerschmidt SI, Moschovakis GL and Forster R: Chemokines and chemokine receptors in lymphoid tissue dynamics. Annu Rev Immunol. 34:203–242. 2016. View Article : Google Scholar : PubMed/NCBI
28	Anders HJ, Romagnani P and Mantovani A: Pathomechanisms: homeostatic chemokines in health, tissue regeneration, and progressive diseases. Trends Mol Med. 20:154–165. 2014. View Article : Google Scholar : PubMed/NCBI
29	Jones GW, Hill DG and Jones SA: Understanding immune cells in tertiary lymphoid organ development: It is all starting to come together. Front Immunol. 7:4012016. View Article : Google Scholar : PubMed/NCBI
30	Willis CR, Seamons A, Maxwell J, Treuting PM, Nelson L, Chen G, Phelps S, Smith CL, Brabb T, Iritani BM and Maggio-Price L: Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis. J Inflamm (Lond). 9:392012. View Article : Google Scholar : PubMed/NCBI
31	Moreno-Viedma V, Amor M, Sarabi A, Bilban M, Staffler G, Zeyda M and Stulnig TM: Common dysregulated pathways in obese adipose tissue and atherosclerosis. Cardiovasc Diabetol. 15:1202016. View Article : Google Scholar : PubMed/NCBI
32	Zhang R, Yang X, Wang J, Han L, Yang A, Zhang J, Zhang D, Li B, Li Z and Xiong Y: Identification of potential biomarkers for differential diagnosis between rheumatoid arthritis and osteoarthritis via integrative genomewide gene expression profiling analysis. Mol Med Rep. 19:30–40. 2019.PubMed/NCBI
33	Tavakolpour S: Interleukin 7 receptor polymorphisms and the risk of multiple sclerosis: A meta-analysis. Mult Scler Relat Disord. 8:66–73. 2016. View Article : Google Scholar : PubMed/NCBI
34	Ciccia F, Rizzo A, Maugeri R, Alessandro R, Croci S, Guggino G, Cavazza A, Raimondo S, Cannizzaro A, Iacopino DG, et al: Ectopic expression of CXCL13, BAFF, APRIL and LT-beta is associated with artery tertiary lymphoid organs in giant cell arteritis. Ann Rheum Dis. 76:235–243. 2017. View Article : Google Scholar : PubMed/NCBI
35	Hong M, Puaux AL, Huang C, Loumagne L, Tow C, Mackay C, Kato M, Prévost-Blondel A, Avril MF, Nardin A and Abastado JP: Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res. 71:6997–7009. 2011. View Article : Google Scholar : PubMed/NCBI
36	van de Pavert SA, Olivier BJ, Goverse G, Vondenhoff MF, Greuter M, Beke P, Kusser K, Höpken UE, Lipp M, Niederreither K, et al: Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat Immunol. 10:1193–1199. 2009. View Article : Google Scholar : PubMed/NCBI