Exploring the mechanism of IgA vasculitis pathogenesis through the interaction of thrombin and inflammatory factors using urinary proteomics

LIU Meng-Meng; HOU Gai-Ling; YANG Xiao-Qing; ZHANG Qiu-Shuang; MEI Xiao-Feng; DING Ying; SONG Lan; HUANG Yan-Jie

doi:10.7499/j.issn.1008-8830.2311151

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Chinese Journal of Contemporary Pediatrics ›› 2024, Vol. 26 ›› Issue (7) : 683-689. DOI: 10.7499/j.issn.1008-8830.2311151

CLINICAL RESEARCH

Exploring the mechanism of IgA vasculitis pathogenesis through the interaction of thrombin and inflammatory factors using urinary proteomics

LIU Meng-Meng, HOU Gai-Ling, YANG Xiao-Qing, ZHANG Qiu-Shuang, MEI Xiao-Feng, DING Ying, SONG Lan, HUANG Yan-Jie

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Abstract

Objective To explore the evidence, urinary biomarkers, and partial mechanisms of hypercoagulability in the pathogenesis of IgA vasculitis (IgAV). Methods Differential expression of proteins in the urine of 10 healthy children and 10 children with IgAV was screened using high-performance liquid chromatography-tandem mass spectrometry, followed by Reactome pathway analysis. Protein-protein interaction (PPI) network analysis was conducted using STRING and Cytoscape software. In the validation cohort, 15 healthy children and 25 children with IgAV were included, and the expression levels of differential urinary proteins were verified using enzyme-linked immunosorbent assay. Results A total of 772 differential proteins were identified between the IgAV group and the control group, with 768 upregulated and 4 downregulated. Reactome pathway enrichment results showed that neutrophil degranulation, platelet activation, and hemostasis pathways were involved in the pathogenesis of IgAV. Among the differential proteins, macrophage migration inhibitory factor (MIF) played a significant role in neutrophil degranulation and hemostasis, while thrombin was a key protein in platelet activation and hemostasis pathways. PPI analysis indicated that thrombin directly interacted with several proteins involved in inflammatory responses, and these interactions involved MIF. Validation results showed that compared to healthy children, children with IgAV had significantly higher urine thrombin/creatinine and urine MIF/creatinine levels (P<0.05). Conclusions Thrombin contributes to the pathogenesis of IgAV through interactions with inflammatory factors. Urinary thrombin and MIF can serve as biomarkers reflecting the hypercoagulable and inflammatory states in children with IgAV.

Key words

IgA vasculitis / Proteomics / Thrombin / Hypercoagulability / Inflammation / Child

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LIU Meng-Meng, HOU Gai-Ling, YANG Xiao-Qing, ZHANG Qiu-Shuang, MEI Xiao-Feng, DING Ying, SONG Lan, HUANG Yan-Jie. Exploring the mechanism of IgA vasculitis pathogenesis through the interaction of thrombin and inflammatory factors using urinary proteomics[J]. Chinese Journal of Contemporary Pediatrics. 2024, 26(7): 683-689 https://doi.org/10.7499/j.issn.1008-8830.2311151

References

1 Trnka P. Henoch-Sch?nlein purpura in children[J]. J Paediatr Child Health, 2013, 49(12): 995-1003. PMID: 24134307. DOI: 10.1111/jpc.12403.
2 Mayer-Hain S, Gebhardt K, Neufeld M, et al. Systemic activation of neutrophils by immune complexes is critical to IgA vasculitis[J]. J Immunol, 2022, 209(6): 1048-1058. PMID: 35985788. DOI: 10.4049/jimmunol.2100924.
3 Giardini AC, Evangelista BG, Sant'Anna MB, et al. Crotalphine attenuates pain and neuroinflammation induced by experimental autoimmune encephalomyelitis in mice[J]. Toxins (Basel), 2021, 13(11): 827. PMID: 34822611. PMCID: PMC8624587. DOI: 10.3390/toxins13110827.
4 McPartland K, Wright G. Acute abdominal pain: Henoch-Sch?nlein purpura case in a young adult, a rare but important diagnosis[J]. Clin Med (Lond), 2019, 19(1): 77-79. PMID: 30651252. PMCID: PMC6399654. DOI: 10.7861/clinmedicine.19-1-77.
5 Grande MA, Belstr?m D, Damgaard C, et al. Salivary concentrations of macrophage activation-related chemokines are influenced by non-surgical periodontal treatment: a 12-week follow-up study[J]. J Oral Microbiol, 2020, 12(1): 1694383. PMID: 31893018. PMCID: PMC6913660. DOI: 10.1080/20002297.2019.1694383.
6 Jaszczura M, Mizga?a-Izworska E, ?wi?tochowska E, et al. Serum levels of selected cytokines [interleukin (IL)-17A, IL-18, IL-23] and chemokines (RANTES, IP10) in the acute phase of immunoglobulin A vasculitis in children[J]. Rheumatol Int, 2019, 39(11): 1945-1953. PMID: 31468124. PMCID: PMC7575498. DOI: 10.1007/s00296-019-04415-4.
7 Kapopara PR, Safikhan NS, Huang JL, et al. CD248 enhances tissue factor procoagulant function, promoting arterial and venous thrombosis in mouse models[J]. J Thromb Haemost, 2021, 19(8): 1932-1947. PMID: 33830628. PMCID: PMC8571649. DOI: 10.1111/jth.15338.
8 Witkowski M, Landmesser U, Rauch U. Tissue factor as a link between inflammation and coagulation[J]. Trends Cardiovasc Med, 2016, 26(4): 297-303. PMID: 26877187. DOI: 10.1016/j.tcm.2015.12.001.
9 马一飞, 李玉峰, 郭桂梅, 等. 新型尿液标志物在紫癜性肾炎患儿中的水平变化[J]. 上海交通大学学报（医学版）, 2020, 40(6): 841-846. DOI: 10.3969/j.issn.1674-8115.2020.06.021.
10 中华医学会儿科学分会免疫学组, 《中华儿科杂志》编辑委员会. 儿童过敏性紫癜循证诊治建议[J]. 中华儿科杂志, 2013, 51(7): 502-507. PMID: 24267130. DOI: 10.3760/cma.j.issn.0578-1310.2013.07.006.
11 Liu Y, Song L, Zheng N, et al. A urinary proteomic landscape of COVID-19 progression identifies signaling pathways and therapeutic options[J]. Sci China Life Sci, 2022, 65(9): 1866-1880. PMID: 35290573. PMCID: PMC8922985. DOI: 10.1007/s11427-021-2070-y.
12 Huang W, Zhan D, Li Y, et al. Proteomics provides individualized options of precision medicine for patients with gastric cancer[J]. Sci China Life Sci, 2021, 64(8): 1199-1211. PMID: 34258712. DOI: 10.1007/s11427-021-1966-4.
13 Jia L, Wu J, Wei J, et al. Proteomic analysis of urine reveals biomarkers for the diagnosis and phenotyping of abdominal-type Henoch-Schonlein purpura[J]. Transl Pediatr, 2021, 10(3): 510-524. PMID: 33850810. PMCID: PMC8039785. DOI: 10.21037/tp-20-317.
14 Fang X, Wu H, Lu M, et al. Urinary proteomics of Henoch-Sch?nlein purpura nephritis in children using liquid chromatography-tandem mass spectrometry[J]. Clin Proteomics, 2020, 17: 10. PMID: 32190014. PMCID: PMC7066733. DOI: 10.1186/s12014-020-09274-x.
15 Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure— definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group[J]. Crit Care, 2004, 8(4): R204-R212. PMID: 15312219. PMCID: PMC522841. DOI: 10.1186/cc2872.
16 Pocock JM, Storisteanu DML, Reeves MB, et al. Human Cytomegalovirus delays neutrophil apoptosis and stimulates the release of a prosurvival secretome[J]. Front Immunol, 2017, 8: 1185. PMID: 28993776. PMCID: PMC5622148. DOI: 10.3389/fimmu.2017.01185.
17 Audemard-Verger A, Pillebout E, Guillevin L, et al. IgA vasculitis (Henoch-Sh?nlein purpura) in adults: diagnostic and therapeutic aspects[J]. Autoimmun Rev, 2015, 14(7): 579-585. PMID: 25688001. DOI: 10.1016/j.autrev.2015.02.003.
18 Dziedzic A, Miller E, Saluk-Bijak J, et al. The molecular aspects of disturbed platelet activation through ADP/P2Y12 pathway in multiple sclerosis[J]. Int J Mol Sci, 2021, 22(12): 6572. PMID: 34207429. PMCID: PMC8234174. DOI: 10.3390/ijms22126572.
19 Zeng FY, Kratzin H, Gabius HJ. Migration inhibitory factor-binding sarcolectin from human placenta is indistinguishable from a subfraction of human serum albumin[J]. Biol Chem Hoppe Seyler, 1994, 375(6): 393-399. PMID: 7980871. DOI: 10.1515/bchm3.1994.375.6.393.
20 Wu M, Schneider DJ, Mayes MD, et al. Osteopontin in systemic sclerosis and its role in dermal fibrosis[J]. J Invest Dermatol, 2012, 132(6): 1605-1614. PMID: 22402440. PMCID: PMC3365548. DOI: 10.1038/jid.2012.32.
21 Murthy S, Karkossa I, Schmidt C, et al. Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages[J]. Cell Death Dis, 2022, 13(1): 53. PMID: 35022393. PMCID: PMC8755842. DOI: 10.1038/s41419-022-04507-3.
22 Luo Y, Yi H, Huang X, et al. Inhibition of macrophage migration inhibitory factor (MIF) as a therapeutic target in bleomycin-induced pulmonary fibrosis rats[J]. Am J Physiol Lung Cell Mol Physiol, 2021, 321(1): L6-L16. PMID: 33881353. DOI: 10.1152/ajplung.00288.2020.
23 Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease[J]. Nature, 1992, 359(6397): 693-699. PMID: 1436033. PMCID: PMC3889166. DOI: 10.1038/359693a0.
24 Kulkarni AB, Huh CG, Becker D, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death[J]. Proc Natl Acad Sci U S A, 1993, 90(2): 770-774. PMID: 8421714. PMCID: PMC45747. DOI: 10.1073/pnas.90.2.770.
25 Janssens R, Struyf S, Proost P. Pathological roles of the homeostatic chemokine CXCL12[J]. Cytokine Growth Factor Rev, 2018, 44: 51-68. PMID: 30396776. DOI: 10.1016/j.cytogfr.2018.10.004.
26 van der Vorst EP, D?ring Y, Weber C. MIF and CXCL12 in cardiovascular diseases: functional differences and similarities[J]. Front Immunol, 2015, 6: 373. PMID: 26257740. PMCID: PMC4508925. DOI: 10.3389/fimmu.2015.00373.
27 Liu L, Liu H, Zhu K, et al. Proteome analysis reveals novel serum biomarkers for Henoch-Sch?nlein purpura in Chinese children[J]. J Proteomics, 2023, 276: 104841. PMID: 36796721. DOI: 10.1016/j.jprot.2023.104841.
28 Tarasuk M, Poungpair O, Ungsupravate D, et al. Human single-chain variable fragment antibody inhibits macrophage migration inhibitory factor tautomerase activity[J]. Int J Mol Med, 2014, 33(3): 515-522. PMID: 24424397. PMCID: PMC3926510. DOI: 10.3892/ijmm.2014.1622.
29 Brown FG, Nikolic-Paterson DJ, Hill PA, et al. Urine macrophage migration inhibitory factor reflects the severity of renal injury in human glomerulonephritis[J]. J Am Soc Nephrol, 2002, 13 (Suppl 1): S7-S13. PMID: 11792756.