吲哚胺2,3-双加氧酶(Indoleamine 2,3-dioxygenase, IDO)是一种具有免疫调节功能并参与色氨酸降解的限速酶,可以通过影响巨噬细胞作用调节炎症反应中的免疫应答,但IDO在烟曲霉菌性角膜炎中的其他免疫调节作用及机制仍不十分明了,因此,本实验在烟曲霉菌感染的小鼠模型及中性粒细胞模型上进行研究。方法:建立小鼠真菌性角膜炎动物模型,记录小鼠角膜炎症评分;采用RT-PCR检测烟曲霉菌菌丝刺激不同时间点的小鼠中性粒细胞中IDO、IDO下游因子AhR及炎症因子(TNF-α, IL-1β, IL-6, IL-10, IL-12) mRNA的表达。采用RT-PCR检测烟曲霉菌灭活菌丝刺激中性粒细胞16小时后各组炎症因子(IL-1β, TNF-α, IL-6) mRNA的表达变化。
Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme that functions as an immunomodulator and participates in the degradation of tryptophan. IDO can regulate the immune response of inflammation by affecting the action of macrophages. However, the immunomodulatory role and mechanism of IDO in Aspergillus fumigatus keratitis are still not very clear. Therefore, this study was conducted on the mouse model of Aspergillus fumigatus infection and the neutrophils model. METHODS: Animal models were developed to measure inflammatory scores and RT-PCR was used to detect the mRNA expression of IDO, downstream factors AHRs of IDO and inflammatory factors (TNF-α, IL-1β, IL-6, IL-10, IL-12) in the cornea of mice stimulated by Aspergillus niacae at different time points. RT-PCR was used to detect the mRNA expression of inflammatory factors (IL-1β, TNF-α, IL-6) in each group after 16 hours of stimulation by Aspergillus fumigatus inactivated hyphae.
Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme that functions as an immunomodulator and participates in the degradation of tryptophan. IDO can regulate the immune response of inflammation by affecting the action of macrophages. However, the immunomodulatory role and mechanism of IDO in Aspergillus fumigatus keratitis are still not very clear. Therefore, this study was conducted on the mouse model of Aspergillus fumigatus infection and the neutrophils model. METHODS: Animal models were developed to measure inflammatory scores and RT-PCR was used to detect the mRNA expression of IDO, downstream factors AHRs of IDO and inflammatory factors (TNF-α, IL-1β, IL-6, IL-10, IL-12) in the cornea of mice stimulated by Aspergillus niacae at different time points. RT-PCR was used to detect the mRNA expression of inflammatory factors (IL-1β, TNF-α, IL-6) in each group after 16 hours of stimulation by Aspergillus fumigatus inactivated hyphae.
参考文献ReferencesCarvalho, A., Cunha, C., Bozza, S., et al. (2012) Immunity and Tolerance to Fungi in Hematopoietic Transplantation: Principles and Perspectives. Frontiers in Immunology, 3, 156.De Luca, A., Bozza, S., Zelante, T., et al. (2010) Non-Hematopoietic Cells Contribute to Protective Tolerance to Aspergillus fumigatus via a TRIF Pathway Converging on IDO. Cellular & Molecular Immunology, 7, 459-470.
<br>https://doi.org/10.1038/cmi.2010.43Romani, L., Bistoni, F., Perruccio, K., et al. (2006) Thymosin Alpha1 Activates Dendritic Cell Tryptophan Catabolism and Establishes a Regulatory Environment for Balance of Inflammation and Tolerance. Blood, 108, 2265-2274.
<br>https://doi.org/10.1182/blood-2006-02-004762Munn, D.H. and Mellor, A.L. (2013) Indoleamine 2,3 Dioxygenase and Metabolic Control of Immune Responses. Trends in Immunology, 34, 137-143. <br>https://doi.org/10.1016/j.it.2012.10.001Mahmoudi, S., Masoomi, A., Ahmadikia, K., et al. (2018) Fungal Keratitis: An Overview of Clinical and Laboratory Aspects. Mycoses, 61, 916-930. <br>https://doi.org/10.1111/myc.12822Manikandan, P., Abdel-Hadi, A., Randhir Babu Singh, Y., Revathi, R., Anita, R., Banawas, S., Bin Dukhyil, A.A., Alshehri, B., Shobana, C.S., Panneer Selvam, K. and Narendran, V. (2019) Fungal Keratitis: Epidemiology, Rapid Detection, and Antifungal Susceptibilities of Fusarium and Aspergillus Isolates from Corneal Scrapings. BioMed Research International, 2019, Article ID: 6395840. <br>https://doi.org/10.1155/2019/6395840Tang, Q., Che, C., Lin, J., He, H., Zhao, W., Lv, L., Zhao, G., et al. (2019) Maresin1 Regulates Neutrophil Recruitment and IL-10 Expression in Aspergillus fumigatus Keratitis. International Immunopharmacology, 69, 103-108.
<br>https://doi.org/10.1016/j.intimp.2019.01.032Wang, L., et al. (2015) Study of Pathogens of Fungal Keratitis and the Sensitivity of Pathogenic Fungi to Therapeutic Agents with the Disk Diffusion Method. Current Eye Research, 40, 1095-1101.
<br>https://doi.org/10.3109/02713683.2015.1056802He, D., et al. (2016) Etiological Analysis of Fungal Keratitis and Rapid Identification of Predominant Fungal Pathogens. Mycopathologia, 181, 75-82. <br>https://doi.org/10.1007/s11046-015-9950-xEl-Zaatari, M., Chang, Y.M., Zhang, M., et al. (2014) Tryptophan Catabolism Restricts IFN-γ-Expressing Neutrophils and Clostridium difficile Immunopathology. The Journal of Immunology, 193, 807-816.
<br>https://doi.org/10.4049/jimmunol.1302913Loughman, J.A., Yarbrough, M.L., Tiemann Kristin, M., et al. (2016) Local Generation of Kynurenines Mediates Inhibition of Neutrophil Chemotaxis by Uropathogenic Escherichia coli. Infection and Immunity, 84, 1176-1183.
<br>https://doi.org/10.1128/IAI.01202-15Niu, Y., Zhao, G., Li, C., Lin, J., Jiang, N., Che, C., Zhang, J., Xu, Q., 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 Ophthalmology & Visual Science, 59, 166-175. <br>https://doi.org/10.1167/iovs.17-21887Jiang, J.Q., Li, C., Cui, C.X., Ma, Y.N., Zhao, G.Q., Peng, X.D., Xu, Q., Wang, Q., Zhu, G.Q., Li, C.Y., et al. (2019) Inhibition of LOX-1 Alleviates the Proinflammatory Effects of High-Mobility Group Box 1 in Aspergillus fumigatus Keratitis. International Journal of Ophthalmology, 12, 898-903. <br>https://doi.org/10.18240/ijo.2019.06.03Wu, T.G., Wilhelmus, K.R. and Mitchell, B.M. (2003) Experimental Keratomycosis in a Mouse Model. Investigative Ophthalmology & Visual Science, 44, 210-216. <br>https://doi.org/10.1167/iovs.02-0446Moreira-Teixeira, L., Stimpson, P.J., Stavropoulos, E., et al. (2020) Type I IFN Exacerbates Disease in Tuberculosis-Susceptible Mice by Inducing Neutrophil-Mediated Lung Inflammation and NETosis. Nature Communications, 11, Article No. 5566. <br>https://doi.org/10.1038/s41467-020-19412-6Pereira, S.A. and Livi, G.P. (1996) Aromatic Amino-Acid Biosynthesis in Candida albicans: Identification of the ARO4 Gene Encoding a Second DAHP Synthase. Current Genetics, 29, 441-445. <br>https://doi.org/10.1007/BF02221512Jiang, N., Zhao, G.Q., Lin, J., et al. (2016) Expression of Indoleamine 2,3-Dioxygenase in a Murine Model of Aspergillus fumigatus Keratitis. International Journal of Ophthalmology, 9, 491-496.Jiang, N., Zhao, G., Lin, J., et al. (2015) Indoleamine 2,3-Dioxygenase Is Involved in the Inflammation Response of Corneal Epithelial Cells to Aspergillus fumigatus Infections. PLoS ONE, 10, e0137423.
<br>https://doi.org/10.1371/journal.pone.0137423Jiang, N., Zhang, L., Zhao, G., et al. (2020) Indoleamine 2,3-Dioxygenase Regulates Macrophage Recruitment, Polarization and Phagocytosis in Aspergillus fumigatus Keratitis. Investigative Ophthalmology & Visual Science, 61, 28.
<br>https://doi.org/10.1167/iovs.61.8.28Zhao, G., Hu, M., Li, C., et al. (2018) Osteopontin Contributes to Effective Neutrophil Recruitment, IL-1β Production and Apoptosis in Aspergillus fumigatus Keratitis. Immunology & Cell Biology, 96, 401-412.
<br>https://doi.org/10.1111/imcb.12010Dickinson, C.M., LeBlanc, B.W., Edhi, M.M., et al. (2018) Leukadherin-1 Ameliorates Endothelial Barrier Damage Mediated by Neutrophils from Critically Ill Patients. Journal of Intensive Care, 6, Article No. 19.
<br>https://doi.org/10.1186/s40560-018-0289-5Zhang, L., Jiang, N., Zhao, G., et al. (2020) Expression and Role of Aryl Hydrocarbon Receptor in Aspergillus fumigatus Keratitis. International Journal of Ophthalmology, 13, 199-205. <br>https://doi.org/10.18240/ijo.2020.02.01Liu, H., Liu, L., Fletcher, B.S., et al. (2006) Novel Action of Indoleamine 2,3-Dioxygenase Attenuating Acute Lung Allograft Injury. American Journal of Respiratory and Critical Care Medicine, 173, 566-72.
<br>https://doi.org/10.1164/rccm.200509-1413OCGriffith, J.W., Sokol, C.L., Luster, A.D., et al. (2014) Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity. Annual Review of Immunology, 32, 659-702.
<br>https://doi.org/10.1146/annurev-immunol-032713-120145Silva, R.L., Lopes, A.H., Guimarães, R.M., et al. (2017) CXCL1/CXCR2 Signaling in Pathological Pain: Role in Peripheral and Central Sensitization. Neurobiology of Disease, 105, 109-116. <br>https://doi.org/10.1016/j.nbd.2017.06.001Planagumà, A., Domènech, T., Pont, M., et al. (2015) Combined Anti CXC Receptors 1 and 2 Therapy Is a Promising Anti-Inflammatory Treatment for Respiratory Diseases by Reducing Neutrophil Migration and Activation. Pulmonary Pharmacology and Therapeutics, 34, 37-45. <br>https://doi.org/10.1016/j.pupt.2015.08.002Takaishi, M., Satoh, T., Akira, S., et al. (2018) Regnase-1, an Immunomodulator, Limits the IL-36/IL-36R Autostimulatory Loop in Keratinocytes to Suppress Skin Inflammation. Journal of Investigative Dermatology, 138, 1439-1442.
<br>https://doi.org/10.1016/j.jid.2017.12.033Guo, J., Tu, J., Hu, Y., et al. (2019) Cathepsin G Cleaves and Activates IL-36 Gamma and Promotes the Inflammation of Psoriasis. Drug Design, Development and Therapy, 13, 581-588. <br>https://doi.org/10.2147/DDDT.S194765Degroote, R.L., Weigand, M., Hauck, S.M., et al. (2019) IL8 and PMA Trigger the Regulation of Different Biological Processes in Granulocyte Activation. Frontiers in Immunology, 10, 3064. <br>https://doi.org/10.3389/fimmu.2019.03064Renassia, C., Louis, S., Cuvellier, S., et al. (2020) Neutrophils from Hereditary Hemochromatosis Patients Are Protected from Iron Excess and Are Primed. Blood Advances, 4, 3853-3863.
<br>https://doi.org/10.1182/bloodadvances.2020002198