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Progranulin通过调控巨噬细胞极化对烟曲霉菌性角膜炎发挥保护作用的研究
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Abstract:
目的：探究progranulin (颗粒蛋白前体，PGRN)在烟曲霉菌角膜炎中发挥抗炎作用的调控机制。方法：建立烟曲霉菌小鼠角膜炎模型，前节照相和临床评分分析PGRN对小鼠角膜病变程度的影响；HE染色检测小鼠角膜组织中炎症细胞的数量；利用CCK-8实验，检测不同浓度梯度的PGRN对小鼠巨噬细胞(RAW264.7)的安全性；实时定量聚合酶链反应(RT-PCR)检测烟曲霉菌感染的细胞中，PGRN对诱导型一氧化氮合酶(iNOS)、趋化因子(CCL2)、精氨酸酶1 (Arg-1) mRNA表达的影响；采用流式细胞术检测PGRN对M2/M1比值的影响。结果：PGRN减轻小鼠烟曲霉菌角膜炎病变程度；PGRN减轻小鼠角膜组织中炎症细胞的浸润；PGRN对RAW264.7细胞无毒；10 ng/ml PGRN处理RAW264.7后显著降低iNOS、CCL2的mRNA表达水平，升高Arg-1的mRNA水平，且PGRN增加了M2/M1的比值。结论：PGRN可能通过调节巨噬细胞极化在烟曲霉菌角膜炎中发挥抗炎作用。
Objective: To investigate the regulatory mechanism by which progranulin (PGRN) exerts anti-inflammatory effects in Aspergillus fumigatus keratitis. Methods: A mouse keratitis model of A. fumigatus was established, and the effects of PGRN on the degree of corneal lesions in mice were analyzed by anterior segment photography and clinical scoring; HE staining was used to detect the number of inflammatory cells in the corneal tissues of mice; using the CCK-8 assay, the safety of PGRN at different concentration gradients on mouse macrophages (RAW264.7) was examined; and real-time quantitative polymerase chain reaction (RT-PCR) detected the effects of PGRN on the mRNA expression of inducible nitric oxide synthase (iNOS), chemokine (CCL2), and arginase 1 (Arg-1) in Aspergillus fumigatus-infected cells; and the effects of PGRN on the M2/M1 ratio were detected by flow cytometry. Results: PGRN attenuated the extent of mouse Aspergillus fumigatus keratitis lesions; PGRN reduced the infiltration of inflammatory cells in mouse corneal tissues; PGRN was nontoxic to RAW264.7 cells; 10 ng/ml PGRN treatment of RAW264.7 significantly decreased the mRNA expression levels of iNOS and CCL2, and markedly elevated the mRNA level of Arg-1, and PGRN increased the M2/M1 ratio. Conclusion: PGRN may exert anti-inflammatory effects in Aspergillus fumigatus keratitis by regulating macrophage polarization.
| [1] | Niu, L., Liu, X., Ma, Z., Yin, Y., Sun, L., Yang, L., et al. (2020) Fungal Keratitis: Pathogenesis, Diagnosis and Prevention. Microbial Pathogenesis, 138, Article 103802. https://doi.org/10.1016/j.micpath.2019.103802 |
| [2] | Soleimani, M., Izadi, A., Khodavaisy, S., Santos, C.O.D., Tehupeiory-Kooreman, M.C., Ghazvini, R.D., et al. (2023) Fungal Keratitis in Iran: Risk Factors, Clinical Features, and Mycological Profile. Frontiers in Cellular and Infection Microbiology, 13, Article 1094182. https://doi.org/10.3389/fcimb.2023.1094182 |
| [3] | Mpakosi, A., Siopi, M., Vrioni, G., Orfanidou, M., Argyropoulou, A., Christofidou, M., et al. (2022) Filamentous Fungal Keratitis in Greece: A 16-Year Nationwide Multicenter Survey. Mycopathologia, 187, 439-453. https://doi.org/10.1007/s11046-022-00666-1 |
| [4] | Tananuvat, N., Upaphong, P., Tangmonkongvoragul, C., Niparugs, M., Chaidaroon, W. and Pongpom, M. (2021) Fungal Keratitis at a Tertiary Eye Care in Northern Thailand: Etiology and Prognostic Factors for Treatment Outcomes. Journal of Infection, 83, 112-118. https://doi.org/10.1016/j.jinf.2021.05.016 |
| [5] | Brown, L., Leck, A.K., Gichangi, M., Burton, M.J. and Denning, D.W. (2021) The Global Incidence and Diagnosis of Fungal Keratitis. The Lancet Infectious Diseases, 21, e49-e57. https://doi.org/10.1016/s1473-3099(20)30448-5 |
| [6] | Heinekamp, T., Schmidt, H., Lapp, K., Pähtz, V., Shopova, I., Köster-Eiserfunke, N., et al. (2014) Interference of Aspergillus Fumigatus with the Immune Response. Seminars in Immunopathology, 37, 141-152. https://doi.org/10.1007/s00281-014-0465-1 |
| [7] | Sharma, N., Bagga, B., Singhal, D., Nagpal, R., Kate, A., Saluja, G., et al. (2022) Fungal Keratitis: A Review of Clinical Presentations, Treatment Strategies and Outcomes. The Ocular Surface, 24, 22-30. https://doi.org/10.1016/j.jtos.2021.12.001 |
| [8] | Raj, N., Vanathi, M., Ahmed, N.H., Gupta, N., Lomi, N. and Tandon, R. (2021) Recent Perspectives in the Management of Fungal Keratitis. Journal of Fungi, 7, Article 907. https://doi.org/10.3390/jof7110907 |
| [9] | Jian, J., Konopka, J. and Liu, C. (2013) Insights into the Role of Progranulin in Immunity, Infection, and Inflammation. Journal of Leukocyte Biology, 93, 199-208. https://doi.org/10.1189/jlb.0812429 |
| [10] | Tang, W., Lu, Y., Tian, Q., Zhang, Y., Guo, F., Liu, G., et al. (2011) The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic against Inflammatory Arthritis in Mice. Science, 332, 478-484. https://doi.org/10.1126/science.1199214 |
| [11] | Wei, F., Zhang, Y., Zhao, W., Yu, X. and Liu, C. (2014) Progranulin Facilitates Conversion and Function of Regulatory T Cells under Inflammatory Conditions. PLOS ONE, 9, e112110. https://doi.org/10.1371/journal.pone.0112110 |
| [12] | Huang, K., Chen, A., Zhang, X., Song, Z., Xu, H., Cao, J., et al. (2015) Progranulin Is Preferentially Expressed in Patients with Psoriasis Vulgaris and Protects Mice from Psoriasis-Like Skin Inflammation. Immunology, 145, 279-287. https://doi.org/10.1111/imm.12446 |
| [13] | Thurner, L., Stöger, E., Fadle, N., Klemm, P., Regitz, E., Kemele, M., et al. (2014) Proinflammatory Progranulin Antibodies in Inflammatory Bowel Diseases. Digestive Diseases and Sciences, 59, 1733-1742. https://doi.org/10.1007/s10620-014-3089-3 |
| [14] | Jian, J., Li, G., Hettinghouse, A. and Liu, C. (2018) Progranulin: A Key Player in Autoimmune Diseases. Cytokine, 101, 48-55. https://doi.org/10.1016/j.cyto.2016.08.007 |
| [15] | Mo, D., Qiu, Y., Tian, B., Liu, X., Chen, Y., Zou, G., et al. (2024) Progranulin Mitigates Intestinal Injury in a Murine Model of Necrotizing Enterocolitis by Suppressing M1 Macrophage Polarization. Cell Biology International, 48, 1520-1532. https://doi.org/10.1002/cbin.12209 |
| [16] | Chen, Y., Wang, C., Xie, K., Lei, M., Chai, Y., Xu, F., et al. (2020) Progranulin Improves Acute Lung Injury through Regulating the Differentiation of Regulatory T Cells and Interleukin-10 Immunomodulation to Promote Macrophage Polarization. Mediators of Inflammation, 2020, 1-15. https://doi.org/10.1155/2020/9704327 |
| [17] | Zhang, L., Nie, F., Zhao, J., Li, S., Liu, W., Guo, H., et al. (2024) PGRN Is Involved in Macrophage M2 Polarization Regulation through TNFR2 in Periodontitis. Journal of Translational Medicine, 22, Article No. 407. https://doi.org/10.1186/s12967-024-05214-7 |
| [18] | Sica, A. and Mantovani, A. (2012) Macrophage Plasticity and Polarization: In Vivo Veritas. Journal of Clinical Investigation, 122, 787-795. https://doi.org/10.1172/jci59643 |
| [19] | Yunna, C., Mengru, H., Lei, W. and Weidong, C. (2020) Macrophage M1/M2 Polarization. European Journal of Pharmacology, 877, Article 173090. https://doi.org/10.1016/j.ejphar.2020.173090 |
| [20] | Qi, P., Liu, X., Li, C., Xu, Q., Hu, L., Duan, H., et al. (2024) Progranulin Protects against Aspergillus fumigatus Keratitis by Attenuating the Inflammatory Response through Enhancing Autophagy. ACS Infectious Diseases, 10, 2826-2835. https://doi.org/10.1021/acsinfecdis.4c00236 |
| [21] | Wu, T.G., Wilhelmus, K.R. and Mitchell, B.M. (2003) Experimental Keratomycosis in a Mouse Model. Investigative Opthalmology & Visual Science, 44, 210-216. https://doi.org/10.1167/iovs.02-0446 |
| [22] | Mills, B., Radhakrishnan, N., Karthikeyan Rajapandian, S.G., Rameshkumar, G., Lalitha, P. and Prajna, N.V. (2021) The Role of Fungi in Fungal Keratitis. Experimental Eye Research, 202, Article 108372. https://doi.org/10.1016/j.exer.2020.108372 |
| [23] | Yang, H., Wang, Q., Han, L., Yang, X., Zhao, W., Lyu, L., et al. (2020) Nerolidol Inhibits the LOX-1/Il-1β Signaling to Protect against the Aspergillus Fumigatus Keratitis Inflammation Damage to the Cornea. International Immunopharmacology, 80, Article 106118. https://doi.org/10.1016/j.intimp.2019.106118 |
| [24] | Jiang, N., Zhang, L., Zhao, G., Lin, J., Wang, Q., Xu, Q., et al. (2020) Indoleamine 2,3-Dioxygenase Regulates Macrophage Recruitment, Polarization and Phagocytosis in Aspergillus fumigatus Keratitis. Investigative Opthalmology & Visual Science, 61, 28. https://doi.org/10.1167/iovs.61.8.28 |
| [25] | Niu, Y., Zhao, G., Li, C., Lin, J., Jiang, N., Che, C., et al. (2018) Aspergillus fumigatus Increased PAR-2 Expression and Elevated Proinflammatory Cytokines Expression through the Pathway of PAR-2/ERK1/2 in Cornea. Investigative Opthalmology & Visual Science, 59, 166-175. https://doi.org/10.1167/iovs.17-21887 |
| [26] | Saeedi-Boroujeni, A., Purrahman, D., Shojaeian, A., Poniatowski, Ł.A., Rafiee, F. and Mahmoudian-Sani, M. (2023) Progranulin (PGRN) as a Regulator of Inflammation and a Critical Factor in the Immunopathogenesis of Cardiovascular Diseases. Journal of Inflammation, 20, Article No. 1. https://doi.org/10.1186/s12950-023-00327-0 |
| [27] | Zhang, T., Feng, T., Wu, K., Guo, J., Nana, A.L., Yang, G., et al. (2023) Progranulin Deficiency Results in Sex-Dependent Alterations in Microglia in Response to Demyelination. Acta Neuropathologica, 146, 97-119. https://doi.org/10.1007/s00401-023-02578-w |
| [28] | Yan, D., Ouyang, W., Lin, J. and Liu, Z. (2023) Smart Coating by Thermo-Sensitive Pluronic F-127 for Enhanced Corneal Healing via Delivery of Biological Macromolecule Progranulin. International Journal of Biological Macromolecules, 253, Article 127586. https://doi.org/10.1016/j.ijbiomac.2023.127586 |
| [29] | Abe, C., Bhaswant, M., Miyazawa, T. and Miyazawa, T. (2023) The Potential Use of Exosomes in Anti-Cancer Effect Induced by Polarized Macrophages. Pharmaceutics, 15, Article 1024. https://doi.org/10.3390/pharmaceutics15031024 |
| [30] | Atri, C., Guerfali, F.Z. and Laouini, D. (2018) Role of Human Macrophage Polarization in Inflammation during Infectious Diseases. International Journal of Molecular Sciences, 19, 1801. https://doi.org/10.3390/ijms19061801 |
| [31] | Wang, C., Ma, C., Gong, L., Guo, Y., Fu, K., Zhang, Y., et al. (2021) Macrophage Polarization and Its Role in Liver Disease. Frontiers in Immunology, 12, Article 803037. https://doi.org/10.3389/fimmu.2021.803037 |
| [32] | Cutolo, M., Campitiello, R., Gotelli, E. and Soldano, S. (2022) The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis. Frontiers in Immunology, 13, Article 867260. https://doi.org/10.3389/fimmu.2022.867260 |
