Exploration of the Shared Gene Signatures and Molecular Mechanisms between Chronic Bronchitis and Antineutrophil Cytoplasmic Antibody-associated Glomerulonephritis: Evidence from Transcriptome Data


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Background:Chronic Bronchitis (CB) is a recurrent and persistent pulmonary inflammation disease. Growing evidence suggests an association between CB and Anti-neutrophil Cytoplasmic Antibody-associated Glomerulonephritis (ANCA-GN). However, the precise mechanisms underlying their association remain unclear.

Aims:The purpose of this study was to further explore the molecular mechanism of the occurrence of chronic bronchitis (CB) associated with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA- GN).

Objective:Our study aimed to investigate the potential shared pathogenesis of CB-associated ANCA-GN.

Methods:Datasets of ANCA (GSE108113 and GSE104948) and CB (GSE151052 and GSE162635) were obtained from the Gene Expression Omnibus (GEO) datasets. Firstly, GSE108113 and GSE151052 were analyzed to identify common differentially expressed genes (DEGs) by Limma package. Based on common DEGs, protein-protein interaction (PPI) network and functional enrichment analyses, including GO, KEGG, and GSEA, were performed. Then, hub genes were identified by degree algorithm and validated in GSE104948 and GSE162635. Further PPI network and functional enrichment analyses were performed on hub genes. Additionally, a competitive ceRNA network was constructed through miRanda and spongeScan. Transcription factors (TFs) were predicted and verified using the TRRUST database. Furthermore, the CIBERSORT algorithm was employed to explore immune cell infiltration. The Drug Gene Interaction Database (DGIDB) was utilized to predict small-molecular compounds of CB and ANCA-GN.

Result:A total of 963 DEGs were identified in the integrated CB dataset, and 610 DEGs were identified in the integrated ANCA-GN dataset. Totally, we identified 22 common DEGs, of which 10 hub genes (LYZ, IRF1, PIK3CG, IL2RG, NT5E, ARG2, HBEGF, NFATC2, ALPL, and FKBP5) were primarily involved in inflammation and immune responses. Focusing on hub genes, we constructed a ceRNA network composed of 323 miRNAs and 348 lncRNAs. Additionally, five TFs (SP1, RELA, NFKB1, HIF1A, and SP3) were identified to regulate the hub genes. Furthermore, immune cell infiltration results revealed immunoregulation in CB and ANCA-GN. Finally, some small-molecular compounds (Daclizumab, Aldesleukin, and NT5E) were predicted to predominantly regulate inflammation and immunity, especially IL-2.

Conclusion:Our study explores the inflammatory-immune pathways underlying CB-associated ANCA-GN and emphasizes the importance of NETs and lymphocyte differentiation, providing novel insights into the shared pathogenesis and therapeutic targets.

Об авторах

Xiaojing Cai

Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Email: info@benthamscience.net

Yueqiang Li

Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Email: info@benthamscience.net

Qingquan Liu

Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Email: info@benthamscience.net

Xiang Gao

Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Email: info@benthamscience.net

Junhua Li

Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Автор, ответственный за переписку.
Email: info@benthamscience.net

Список литературы

  1. Kitching AR, Anders HJ, Basu N, et al. ANCA-associated vasculitis. Nat Rev Dis Primers 2020; 6(1): 71. doi: 10.1038/s41572-020-0204-y PMID: 32855422
  2. Nakazawa D, Masuda S, Tomaru U, Ishizu A. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol 2019; 15(2): 91-101. doi: 10.1038/s41584-018-0145-y PMID: 30542206
  3. Luan J, Xing G. Pathogenesis of antimicrobial peptides LL-37 and CpG-ODN in ANCA associated vasculitis. J Nephrol 2017; 30(1): 63-71. doi: 10.1007/s40620-016-0336-z PMID: 27476166
  4. Galateau F, Loire R, Capron F, et al. Pulmonary lesions in Wegener’s disease. Report of the French Anatomo-clinical Research Group. Study of 40 pulmonary biopsies. Rev Mal Respir 1992; 9(4): 431-42. PMID: 1509187
  5. Turgeon D, Balter MS, Pagnoux C. Interstitial lung disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis: An update on pathogenesis and treatment. Curr Opin Pulm Med 2023; 29(5): 436-42. doi: 10.1097/MCP.0000000000000979 PMID: 37395510
  6. Konstantinov KN, Ulff-Møller CJ, Tzamaloukas AH. Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms. Autoimmun Rev 2015; 14(3): 201-3. doi: 10.1016/j.autrev.2014.10.020 PMID: 25448042
  7. Tian Y, Zeng T, Tan L, et al. Clinical significance of BPI-ANCA detecting in COPD patients with Pseudomonas aeruginosa colonization. J Clin Lab Anal 2019; 33(6): e22908. doi: 10.1002/jcla.22908 PMID: 31106488
  8. Mohammad AJ, Segelmark M. A population-based study showing better renal prognosis for proteinase 3 antineutrophil cytoplasmic antibody (ANCA)-associated nephritis versus myeloperoxidase ANCA-associated nephritis. J Rheumatol 2014; 41(7): 1366-73. doi: 10.3899/jrheum.131038 PMID: 24882836
  9. Kronbichler A, Jayne DRW. ANCA renal risk score: Is prediction of end-stage renal disease at baseline possible? Kidney Int 2018; 94(6): 1045-7. doi: 10.1016/j.kint.2018.10.001 PMID: 30466561
  10. Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007; 176(2): 231-41. doi: 10.1083/jcb.200606027 PMID: 17210947
  11. Tao M, He Y, Li L, et al. Identification and validation of immune-associated NETosis subtypes and biomarkers in anti-neutrophil cytoplasmic antibody associated glomerulonephritis. Front Immunol 2023; 14: 1177968. doi: 10.3389/fimmu.2023.1177968 PMID: 37465687
  12. Thiam HR, Wong SL, Wagner DD, Waterman CM. Cellular mechanisms of NETosis. Annu Rev Cell Dev Biol 2020; 36(1): 191-218. doi: 10.1146/annurev-cellbio-020520-111016 PMID: 32663035
  13. Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 2010; 207(9): 1853-62. doi: 10.1084/jem.20100239 PMID: 20733033
  14. Wang ZL, Shang JC, Li CM, Li M, Xing GQ. Significance of serum peptidylarginine deiminase type 4 in ANCA-associated vasculitis. Beijing Da Xue Xue Bao 2014; 46(2): 200-6. PMID: 24743806
  15. Guang-Qun LHX. Neutrophil extracellular traps induce production of MPO-ANCA in chronic bronchitis rats. Chin J Immunol 2017; 33: 1458-63.
  16. Edgar R, Domrachev M, Lash AE. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 2002; 30(1): 207-10. doi: 10.1093/nar/30.1.207 PMID: 11752295
  17. Yao M, Zhang C, Gao C, et al. Exploration of the shared gene signatures and molecular mechanisms between systemic lupus erythematosus and pulmonary arterial hypertension: Evidence from transcriptome data. Front Immunol 2021; 12: 658341. doi: 10.3389/fimmu.2021.658341 PMID: 34335565
  18. Su W, Zhao Y, Wei Y, Zhang X, Ji J, Yang S. Exploring the pathogenesis of psoriasis complicated with atherosclerosis via microarray data analysis. Front Immunol 2021; 12: 667690. doi: 10.3389/fimmu.2021.667690 PMID: 34122426
  19. Yu G, Wang LG, Han Y, He QY. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 2012; 16(5): 284-7. doi: 10.1089/omi.2011.0118 PMID: 22455463
  20. Shibata S, Tada Y, Hau CS, et al. Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells. Nat Commun 2015; 6(1): 7687. doi: 10.1038/ncomms8687 PMID: 26173479
  21. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102(43): 15545-50. doi: 10.1073/pnas.0506580102 PMID: 16199517
  22. Han H, Cho JW, Lee S, et al. TRRUST v2: An expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res 2018; 46(D1): D380-6. doi: 10.1093/nar/gkx1013 PMID: 29087512
  23. Wang Z, Zhang Y, Li K. Nuclear miRNAs as transcriptional regulators in processes related to various cancers (Review). Int J Oncol 2024; 64(5): 56. doi: 10.3892/ijo.2024.5644 PMID: 38606502
  24. Cao Y, Tang W, Tang W. Immune cell infiltration characteristics and related core genes in lupus nephritis: Results from bioinformatic analysis. BMC Immunol 2019; 20(1): 37. doi: 10.1186/s12865-019-0316-x PMID: 31638917
  25. Griffith M, Griffith OL, Coffman AC, et al. DGIdb: Mining the druggable genome. Nat Methods 2013; 10(12): 1209-10. doi: 10.1038/nmeth.2689 PMID: 24122041
  26. Kadowaki T, Yano S, Yamadori I, et al. A case of sinobronchial syndrome complicated with myeloperoxidase antineutrophil cytoplasmic antibody associated vasculitis: Review of the literature. Intern Med 2012; 51(7): 763-7. doi: 10.2169/internalmedicine.51.5957 PMID: 22466835
  27. Ha H, Debnath B, Neamati N. Role of the CXCL8-CXCR1/2 axis in cancer and inflammatory diseases. Theranostics 2017; 7(6): 1543-88. doi: 10.7150/thno.15625 PMID: 28529637
  28. Sung PS, Hsieh SL. C-type lectins and extracellular vesicles in virus-induced NETosis. J Biomed Sci 2021; 28(1): 46. doi: 10.1186/s12929-021-00741-7 PMID: 34116654
  29. Fischer S, Stegmann F, Gnanapragassam VS, Lepenies B. From structure to function – Ligand recognition by myeloid C-type lectin receptors. Comput Struct Biotechnol J 2022; 20: 5790-812. doi: 10.1016/j.csbj.2022.10.019 PMID: 36382179
  30. Takeuchi A, Saito T. CD4 CTL, a cytotoxic subset of CD4+ T cells, their differentiation and function. Front Immunol 2017; 8: 194. doi: 10.3389/fimmu.2017.00194 PMID: 28280496
  31. Behler-Janbeck F, Takano T, Maus R, et al. C-type lectin mincle recognizes glucosyl-diacylglycerol of streptococcus pneumoniae and plays a protective role in pneumococcal pneumonia. PLoS Pathog 2016; 12(12): e1006038. doi: 10.1371/journal.ppat.1006038 PMID: 27923071
  32. Schreiber A, Rousselle A, Becker JU, von Mässenhausen A, Linkermann A, Kettritz R. Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis. Proc Natl Acad Sci USA 2017; 114(45): E9618-25. doi: 10.1073/pnas.1708247114 PMID: 29078325
  33. Fiorini G, Crespi S, Rinaldi M, Oberti E, Vigorelli R, Palmieri G. Serum ECP and MPO are increased during exacerbations of chronic bronchitis with airway obstruction. Biomed Pharmacother 2000; 54(5): 274-8. doi: 10.1016/S0753-3322(00)80071-2 PMID: 10917466
  34. Söderberg D, Segelmark M. Neutrophil extracellular traps in ANCA-associated vasculitis. Front Immunol 2016; 7: 256. doi: 10.3389/fimmu.2016.00256 PMID: 27446086
  35. O’Sullivan KM, Holdsworth SR. Neutrophil extracellular traps: A potential therapeutic target in MPO-ANCA associated vasculitis? Front Immunol 2021; 12: 635188. doi: 10.3389/fimmu.2021.635188 PMID: 33790907
  36. Juha M, Molnár A, Jakus Z, Ledó N. NETosis: An emerging therapeutic target in renal diseases. Front Immunol 2023; 14: 1253667. doi: 10.3389/fimmu.2023.1253667 PMID: 37744367
  37. d’Alessandro M, Conticini E, Bergantini L, et al. Neutrophil extracellular traps in ANCA-associated vasculitis and interstitial lung disease: A scoping review. Life 2022; 12(2): 317. doi: 10.3390/life12020317 PMID: 35207604
  38. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: The leukocyte adhesion cascade updated. Nat Rev Immunol 2007; 7(9): 678-89. doi: 10.1038/nri2156 PMID: 17717539
  39. Di Stefano A, Maestrelli P, Roggeri A, et al. Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am J Respir Crit Care Med 1994; 149(3): 803-10. doi: 10.1164/ajrccm.149.3.7509705 PMID: 7509705
  40. Kuligowski MP, Kwan RYQ, Lo C, et al. Antimyeloperoxidase antibodies rapidly induce α4-integrin–dependent glomerular neutrophil adhesion. Blood 2009; 113(25): 6485-94. doi: 10.1182/blood-2008-12-192617 PMID: 19383970
  41. Soehnlein O, Zernecke A, Weber C. Neutrophils launch monocyte extravasation by release of granule proteins. Thromb Haemost 2009; 102(2): 198-205. PMID: 19652869
  42. Ji J, Ganguly K, Mihai X, et al. Exposure of normal and chronic bronchitis-like mucosa models to aerosolized carbon nanoparticles: Comparison of pro-inflammatory oxidative stress and tissue injury/repair responses. Nanotoxicology 2019; 13(10): 1362-79. doi: 10.1080/17435390.2019.1655600 PMID: 31462114
  43. Sanders JSF, van Goor H, Hanemaaijer R, Kallenberg CGM, Stegeman CA. Renal expression of matrix metalloproteinases in human ANCA-associated glomerulonephritis. Nephrol Dial Transplant 2004; 19(6): 1412-9. doi: 10.1093/ndt/gfh186 PMID: 15034162
  44. Liu Y, Feng Y, Kong X, et al. A microRNA sponge, LINC02193, promotes neutrophil activation by upregulating ICAM1 and is correlated with ANCA-associated vasculitis. Rheumatology 2023; kead605.
  45. Rahman SMT, Singh A, Lowe S, et al. Co-imaging of RelA and c-Rel reveals features of NF-κB signaling for ligand discrimination. Cell Rep 2024; 43(3): 113940. doi: 10.1016/j.celrep.2024.113940 PMID: 38483906
  46. Huang D, Chen J, Yang L, et al. NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death. Nat Immunol 2018; 19(10): 1112-25. doi: 10.1038/s41590-018-0207-y PMID: 30224822
  47. Ragland SA, Criss AK. From bacterial killing to immune modulation: Recent insights into the functions of lysozyme. PLoS Pathog 2017; 13(9): e1006512. doi: 10.1371/journal.ppat.1006512 PMID: 28934357
  48. Kimura R, Matsuzawa N, Arimura Y, Soejima A, Nakabayashi K, Yamada A. Azurocidin-specific-ANCA-related idiopathic necrotizing crescentic glomerulonephritis. Am J Kidney Dis 2004; 43(4): e17.1-4. doi: 10.1053/j.ajkd.2003.12.038 PMID: 15042565
  49. Zhang L, Rice AB, Adler K, et al. Vanadium stimulates human bronchial epithelial cells to produce heparin-binding epidermal growth factor-like growth factor: A mitogen for lung fibroblasts. Am J Respir Cell Mol Biol 2001; 24(2): 123-31. doi: 10.1165/ajrcmb.24.2.4096 PMID: 11159045
  50. Ntinopoulou M, Cassimos D, Roupakia E, et al. Ιnterleukin-17A-enriched neutrophil extracellular traps promote immunofibrotic aspects of childhood asthma exacerbation. Biomedicines 2023; 11(8): 2104. doi: 10.3390/biomedicines11082104 PMID: 37626601
  51. Gaudin PB, Askin FB, Falk RJ, Jennette JC. The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and anti-myeloperoxidase. Am J Clin Pathol 1995; 104(1): 7-16. doi: 10.1093/ajcp/104.1.7 PMID: 7611186
  52. Chrysanthopoulou A, Mitroulis I, Apostolidou E, et al. Neutrophil extracellular traps promote differentiation and function of fibroblasts. J Pathol 2014; 233(3): 294-307. doi: 10.1002/path.4359 PMID: 24740698
  53. Fleisch H, Bisaz S. Mechanism of calcification: Inhibitory role of pyrophosphate. Nature 1962; 195(4844): 911. doi: 10.1038/195911a0 PMID: 13893487
  54. Bobryshev Y, Orekhov A, Sobenin I, Chistiakov D. Role of bone- type tissue-nonspecific alkaline phosphatase and PHOSPO1 in vascular calcification. Curr Pharm Des 2014; 20(37): 5821-8. doi: 10.2174/1381612820666140212193011 PMID: 24533943
  55. Peters E, Geraci S, Heemskerk S, et al. Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate. Br J Pharmacol 2015; 172(20): 4932-45. doi: 10.1111/bph.13261 PMID: 26222228
  56. Davidson JA, Urban T, Tong S, et al. Alkaline phosphatase, soluble extracellular adenine nucleotides, and adenosine production after infant cardiopulmonary bypass. PLoS One 2016; 11(7): e0158981. doi: 10.1371/journal.pone.0158981 PMID: 27384524
  57. Misumi Y, Ogata S, Ohkubo K, Hirose S, Ikehara Y. Primary structure of human placental 5′-nucleotidase and identification of the glycolipid anchor in the mature form. Eur J Biochem 1990; 191(3): 563-9. doi: 10.1111/j.1432-1033.1990.tb19158.x PMID: 2129526
  58. van Heusden C, Grubb B, Button B, Lazarowski E. Airway epithelial nucleotide release contributes to mucociliary clearance. Life 2021; 11(5): 430. doi: 10.3390/life11050430 PMID: 34064654
  59. Kling L, Benck U, Breedijk A, et al. Changes in CD73, CD39 and CD26 expression on T-lymphocytes of ANCA-associated vasculitis patients suggest impairment in adenosine generation and turn-over. Sci Rep 2017; 7(1): 11683. doi: 10.1038/s41598-017-12011-4 PMID: 28916770
  60. Brunini F, Page TH, Gallieni M, Pusey CD. The role of monocytes in ANCA-associated vasculitides. Autoimmun Rev 2016; 15(11): 1046-53. doi: 10.1016/j.autrev.2016.07.031 PMID: 27491570
  61. Whittaker L, Niu N, Temann UA, et al. Interleukin-13 mediates a fundamental pathway for airway epithelial mucus induced by CD4 T cells and interleukin-9. Am J Respir Cell Mol Biol 2002; 27(5): 593-602. doi: 10.1165/rcmb.4838 PMID: 12397019
  62. Moran SM, Monach PA, Zgaga L, et al. Urinary soluble CD163 and monocyte chemoattractant protein-1 in the identification of subtle renal flare in anti-neutrophil cytoplasmic antibody-associated vasculitis. Nephrol Dial Transplant 2020; 35(2): 283-91. doi: 10.1093/ndt/gfy300 PMID: 30380100
  63. Santana KG, Righetti RF, Breda CNS, et al. Cholesterol-ester transfer protein alters M1 and M2 macrophage polarization and worsens experimental elastase-induced pulmonary emphysema. Front Immunol 2021; 12: 684076. doi: 10.3389/fimmu.2021.684076 PMID: 34367144
  64. Kang MJ, Choi JM, Kim BH, et al. IL-18 induces emphysema and airway and vascular remodeling via IFN-γ, IL-17A, and IL-13. Am J Respir Crit Care Med 2012; 185(11): 1205-17. doi: 10.1164/rccm.201108-1545OC PMID: 22383501
  65. Akitsu A, Iwakura Y. Interleukin-17-producing γδ T ( γδ 17) cells in inflammatory diseases. Immunology 2018; 155(4): 418-26. doi: 10.1111/imm.12993 PMID: 30133701
  66. Free ME, Stember KG, Hess JJ, et al. Restricted myeloperoxidase epitopes drive the adaptive immune response in MPO-ANCA vasculitis. J Autoimmun 2020; 106: 102306. doi: 10.1016/j.jaut.2019.102306 PMID: 31383567
  67. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of TH17 cells. Nature 2008; 453(7198): 1051-7. doi: 10.1038/nature07036 PMID: 18563156
  68. Siddiqui RA, Atta-ur-Rahman, Interleukin-8: An autocrine inflammatory mediator. Curr Pharm Des 1999; 5(4): 241-53. doi: 10.2174/1381612805666230109213039
  69. Meuth SG, Göbel K, Wiendl H. Immune therapy of multiple sclerosis-future strategies. Curr Pharm Des 2012; 18(29): 4489-97. doi: 10.2174/138161212802502198 PMID: 22612746
  70. Busse WW, Israel E, Nelson HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: A randomized, controlled trial. Am J Respir Crit Care Med 2008; 178(10): 1002-8. doi: 10.1164/rccm.200708-1200OC PMID: 18787222
  71. Cassell D, Choudhri S, Humphrey R, Martell R, Reynolds T, Shanafelt A. Therapeutic enhancement of IL-2 through molecular design. Curr Pharm Des 2002; 8(24): 2171-83. doi: 10.2174/1381612023393260 PMID: 12369861
  72. Mullard A. Restoring IL-2 to its cancer immunotherapy glory. Nat Rev Drug Discov 2021; 20(3): 163-5. doi: 10.1038/d41573-021-00034-6 PMID: 33603157
  73. Shen H, Yang E, Guo M, et al. Adjunctive Zoledronate + IL-2 administrations enhance anti-tuberculosis Vγ2Vδ2 T-effector populations, and improve treatment outcome of multidrug-resistant tuberculosis. Emerg Microbes Infect 2022; 11(1): 1790-805. doi: 10.1080/22221751.2022.2095930 PMID: 35765887
  74. Jiang S, Liu Y, Lu C, Li Y, Venners SA. Associations of two common polymorphisms in MTHFR gene with blood lipids and therapeutic efficacy of simvastatin. Curr Pharm Des 2022; 28(26): 2167-76. doi: 10.2174/1381612828666220623102537 PMID: 35747958
  75. Choi M, Rolle S, Rane M, Haller H, Luft FC, Kettritz R. Extracellular signal-regulated kinase inhibition by statins inhibits neutrophil activation by ANCA. Kidney Int 2003; 63(1): 96-106. doi: 10.1046/j.1523-1755.2003.00718.x PMID: 12472772
  76. Zycinska K, Wardyn KA, Zielonka TM, Krupa R, Lukas W. Co-trimoxazole and prevention of relapses of PR3-ANCA positive vasculitis with pulmonary involvement. Eur J Med Res 2009; 14 (Suppl. 4): 265-7. doi: 10.1186/2047-783X-14-S4-265 PMID: 20156769

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