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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 繆希椿(Shi-Chuen Miaw) | |
| dc.contributor.author | Tsun Wai Chow | en |
| dc.contributor.author | 周浚煒 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:02:47Z | - |
| dc.date.available | 2026-08-10 | |
| dc.date.available | 2022-11-24T03:02:47Z | - |
| dc.date.copyright | 2021-08-18 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-03 | |
| dc.identifier.citation | Abdelaziz, M.H., Abdelwahab, S.F., Wan, J., Cai, W., Huixuan, W., Jianjun, C., Kumar, K.D., Vasudevan, A., Sadek, A., Su, Z., et al. (2020). Alternatively activated macrophages; a double-edged sword in allergic asthma. J Transl Med 18, 58. Bess, E., Fisslthaler, B., Fromel, T., and Fleming, I. (2011). Nitric oxide-induced activation of the AMP-activated protein kinase alpha2 subunit attenuates IkappaB kinase activity and inflammatory responses in endothelial cells. PLoS One 6, e20848. Bosca, L., Gonzalez-Ramos, S., Prieto, P., Fernandez-Velasco, M., Mojena, M., Martin-Sanz, P., and Alemany, S. (2015). Metabolic signatures linked to macrophage polarization: from glucose metabolism to oxidative phosphorylation. Biochem Soc Trans 43, 740-744. Burke, B., Tang, N., Corke, K.P., Tazzyman, D., Ameri, K., Wells, M., and Lewis, C.E. (2002). Expression of HIF-I alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy. Journal of Pathology 196, 204-212. Carling, D. (2004). The AMP-activated protein kinase cascade--a unifying system for energy control. Trends Biochem Sci 29, 18-24. Cassado, A.D., Lima, M.R.D., and Bortoluci, K.R. (2015). Revisiting mouse peritoneal macrophages: heterogeneity, development, and function. Front. Immunol. 6, 9. Cavaillon, J.M. (2011). The historical milestones in the understanding of leukocyte biology initiated by Elie Metchnikoff. J Leukoc Biol 90, 413-424. Chandrasekar, B., Boylston, W.H., Venkatachalam, K., Webster, N.J., Prabhu, S.D., and Valente, A.J. (2008). Adiponectin blocks interleukin-18-mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-kappaB/PTEN suppression. J Biol Chem 283, 24889-24898. Chawla, A. (2010). Control of macrophage activation and function by PPARs. Circ Res 106, 1559-1569. Chin, W.Y., He, C.Y., Chow, T.W., Yu, Q.Y., Lai, L.C., and Miaw, S.C. (2021). Adenylate Kinase 4 Promotes Inflammatory Gene Expression via Hif1alpha and AMPK in Macrophages. Front Immunol 12, 630318. Dupre-Crochet, S., Erard, M., and Nubetae, O. (2013). ROS production in phagocytes: why, when, and where? J Leukoc Biol 94, 657-670. Dzeja, P., and Terzic, A. (2009). Adenylate kinase and AMP signaling networks: metabolic monitoring, signal communication and body energy sensing. Int J Mol Sci 10, 1729-1772. Elhelu, M.A. (1983). The role of macrophages in immunology. J. Natl. Med. Assoc. 75, 314-317. Fajriah, S., Handayani, S., Sinurat, E., Megawati, M., Darmawan, A., Hariyanti, H., Dewi, R.T., and Septama, A.W. (2020). In vitro Immunomodulatory Effect from Edible Green Seaweed of Caulerpa lentillifera Extracts on Nitric Oxide Production and Phagocytosis Activity of RAW 264.7 Murine Macrophage Cells. J. Young Pharm. 12, 334-337. Franchini, A., Fontanili, P., and Ottaviani, E. (1995). Invertebrate immunocytes: relationship between phagocytosis and nitric oxide production. Comparative Biochemistry and Physiology B-Biochemistry Molecular Biology 110, 403-407. Freeman, S.A., and Grinstein, S. (2014). Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol. Rev. 262, 193-215. Fujisawa, K., Terai, S., Takami, T., Yamamoto, N., Yamasaki, T., Matsumoto, T., Yamaguchi, K., Owada, Y., Nishina, H., Noma, T., and Sakaida, I. (2016). Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4. J Exp Clin Cancer Res 35, 48. Gordon, S. (2003). Alternative activation of macrophages. Nat Rev Immunol 3, 23-35. Green, C.J., Macrae, K., Fogarty, S., Hardie, D.G., Sakamoto, K., and Hundal, H.S. (2011). Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor kappaB signalling in rat skeletal muscle cells by AMP-activated protein kinase. Biochem J 435, 463-474. Hu, C.J., Iyer, S., Sataur, A., Covello, K.L., Chodosh, L.A., and Simon, M.C. (2006). Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells. Mol Cell Biol 26, 3514-3526. Huang, H., and Zhao, Z. (2019). Transduction with lentiviral vectors altered the expression profile of host MicroRNAs. Eur. J. Immunol. 49, 1080-1081. Italiani, P., and Boraschi, D. (2014). From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation. Front Immunol 5, 514. Jamaati, H., Mortaz, E., Pajouhi, Z., Folkerts, G., Movassaghi, M., Moloudizargari, M., Adcock, I.M., and Garssen, J. (2017). Nitric Oxide in the Pathogenesis and Treatment of Tuberculosis. Front Microbiol 8, 2008. Jan, Y.H., Lai, T.C., Yang, C.J., Lin, Y.F., Huang, M.S., and Hsiao, M. (2019). Adenylate kinase 4 modulates oxidative stress and stabilizes HIF-1alpha to drive lung adenocarcinoma metastasis. J Hematol Oncol 12, 12. Jiang, L., Wang, M., Lin, S., Jian, R., Li, X., Chan, J., Dong, G., Fang, H., Robinson, A.E., Consortium, G.T., and Snyder, M.P. (2020). A Quantitative Proteome Map of the Human Body. Cell 183, 269-283 e219. Khoo, J.C., and Russell, P.J. (1972). Isoenzymes of adenylate kinase in human tissue. Biochimica Et Biophysica Acta 268, 98- . Klepinin, A., Zhang, S., Klepinina, L., Rebane-Klemm, E., Terzic, A., Kaambre, T., and Dzeja, P. (2020). Adenylate Kinase and Metabolic Signaling in Cancer Cells. Front Oncol 10, 660. Klepinin, A., Zhang, S., Vuckovic, I., Kaambre, T., Macura, S., and Dzeja, P. (2017). Stable isotope 18O-assisted dynamic phosphometabolomic of adenylate kinase phosphotransfer and nucleotide triphosphate metabolism. Febs Journal 284, 371-372. Klinghoffer, R.A., Magnus, J., Schelter, J., Mehaffey, M., Coleman, C., and Cleary, M.A. (2010). Reduced seed region-based off-target activity with lentivirus-mediated RNAi. RNA 16, 879-884. Kopec, K.K., and Carroll, R.T. (2000). Phagocytosis is regulated by nitric oxide in murine microglia. Nitric Oxide 4, 103-111. Kumar, A., Barrett, J.P., Alvarez-Croda, D.M., Stoica, B.A., Faden, A.I., and Loane, D.J. (2016). NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury. Brain Behav Immun 58, 291-309. Leopold Wager, C.M., and Wormley, F.L., Jr. (2014). Classical versus alternative macrophage activation: the Ying and the Yang in host defense against pulmonary fungal infections. Mucosal Immunol 7, 1023-1035. Ley, K. (2017). M1 Means Kill; M2 Means Heal. J Immunol 199, 2191-2193. Liu, R., Strom, A.L., Zhai, J., Gal, J., Bao, S., Gong, W., and Zhu, H. (2009). Enzymatically inactive adenylate kinase 4 interacts with mitochondrial ADP/ATP translocase. Int J Biochem Cell Biol 41, 1371-1380. Liu, Y., Beyer, A., and Aebersold, R. (2016). On the Dependency of Cellular Protein Levels on mRNA Abundance. Cell 165, 535-550. Louwe, P.A., Badiola Gomez, L., Webster, H., Perona-Wright, G., Bain, C.C., Forbes, S.J., and Jenkins, S.J. (2021). Recruited macrophages that colonize the post-inflammatory peritoneal niche convert into functionally divergent resident cells. Nat Commun 12, 1770. Luckett-Chastain, L., Calhoun, K., Schartz, T., and Gallucci, R.M. (2016). IL-6 influences the balance between M1 and M2 macrophages in a mouse model of irritant contact dermatitis. Journal of Immunology 196. Majmundar, A.J., Wong, W.H.J., and Simon, M.C. (2010). Hypoxia-Inducible Factors and the Response to Hypoxic Stress. Mol. Cell 40, 294-309. Martinez, F.O., Sica, A., Mantovani, A., and Locati, M. (2008). Macrophage activation and polarization. Frontiers in Bioscience-Landmark 13, 453-461. Nathan, C. (2006). Role of iNOS in human host defense. Science 312, 1874-1874. Noma, T. (2005). Dynamics of nucleotide metabolism as a supporter of life phenomena. The journal of medical investigation, 127-136. Odegaard, J.I., and Chawla, A. (2008). Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab 4, 619-626. Panayiotou, C., Solaroli, N., and Karlsson, A. (2014). The many isoforms of human adenylate kinases. Int J Biochem Cell Biol 49, 75-83. Rendra, E., Riabov, V., Mossel, D.M., Sevastyanova, T., Harmsen, M.C., and Kzhyshkowska, J. (2019). Reactive oxygen species (ROS) in macrophage activation and function in diabetes. Immunobiology 224, 242-253. Sag, D., Carling, D., Stout, R.D., and Suttles, J. (2008). Adenosine 5'-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol 181, 8633-8641. Tannahill, G.M., Curtis, A.M., Adamik, J., Palsson-McDermott, E.M., McGettrick, A.F., Goel, G., Frezza, C., Bernard, N.J., Kelly, B., Foley, N.H., et al. (2013). Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238-242. Tavakoli, S., and Asmis, R. (2012). Reactive Oxygen Species and Thiol Redox Signaling in the Macrophage Biology of Atherosclerosis. Antioxidants Redox Signaling 17, 1785-1795. Thapa, B., and Lee, K. (2019). Metabolic influence on macrophage polarization and pathogenesis. BMB Reports 52, 360-372. Uribe-Querol, E., and Rosales, C. (2020). Phagocytosis: Our Current Understanding of a Universal Biological Process. Front Immunol 11, 1066. van den Biggelaar, R., van Eden, W., Rutten, V., and Jansen, C.A. (2020). Nitric Oxide Production and Fc Receptor-Mediated Phagocytosis as Functional Readouts of Macrophage Activity upon Stimulation with Inactivated Poultry Vaccines in Vitro. Vaccines 8, 16. van Iwaarden, J.F., Claassen, E., Jeurissen, S.H.M., Haagsman, H.P., and Kraal, G. (2001). Alveolar macrophages, surfactant lipids, and surfactant protein B regulate the induction of immune responses via the airways. American Journal of Respiratory Cell and Molecular Biology 24, 452-458. Wang, G.L., Jiang, B.H., Rue, E.A., and Semenza, G.L. (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the United States of America 92, 5510-5514. Weischenfeldt, J., and Porse, B. (2008). Bone Marrow-Derived Macrophages (BMM): Isolation and Applications. CSH Protoc 2008, pdb prot5080. Witting, A., Muller, P., Herrmann, A., Kettenmann, H., and Nolte, C. (2000). Phagocytic clearance of apoptotic neurons by microglia/brain macrophages in vitro: Involvement of lectin-, integrin-, and phosphatidylserine-mediated recognition. Journal of Neurochemistry 75, 1060-1070. Xu, J., Ji, J., and Yan, X.H. (2012). Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr 52, 373-381. Ying, W., Cheruku, P.S., Bazer, F.W., Safe, S.H., and Zhou, B. (2013). Investigation of macrophage polarization using bone marrow derived macrophages. J Vis Exp. Yoneda, T., Sato, M., Maeda, M., Takagi, H (1998). Identification of a novel adenylate kinase system in the brain: Cloning of the fourth adenylate kinase. Molecular Brain Research 62, 187–195. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80223 | - |
| dc.description.abstract | 巨噬細胞（也稱為Mφ，MΦ或MP）是由Ilya Metchnikoff於19世紀首次發現的，根據明顯的表現型和功能將其分為經典活化巨噬細胞（M1）和交替激活巨噬細胞（M2），在免疫系統和免疫反應中扮演不可缺少的角色。經典活化的巨噬細胞（M1）由脂多醣（LPS）及干擾素-γ（IFN-γ）誘導，並表達高水平的促發炎細胞因子，例如介白素-1（IL-1），介白素-6（IL-6），腫瘤壞死因子-α（TNF-α）。被介白素-4（IL-4）及介白素-13（IL-13）激活的巨噬細胞稱為交替激活巨噬細胞（AAM）或M2巨噬細胞。 M2巨噬細胞產生介白素-10（IL-10），負責組織修復與維持和抗發炎反應。腺苷酸激酶4（Ak4）是腺苷酸激酶家族的成員，在粒線體的基質中表達。它參與細胞腺嘌呤核苷酸的能量代謝和衡定。它們催化γ-磷酸基團從ATP（或GTP）可逆地轉移到AMP，釋放ADP（或GDP）和ADP。但是Ak4在巨噬細胞的功能尚未釐清。我們發現與其他巨噬細胞亞型(包括M0和M2)相比，Ak4的表達在M1中被高度誘導。為了進一步研究Ak4在M1巨噬細胞中的功能，在M0巨噬細胞中以Ak4 shRNA處理，敲低（KD）了Ak4的表現，這些巨噬細胞進一步被LPS及IFN-γ刺激而極化成M1。M1在敲低（KD）Ak4下，Nos2，Hifla，Il1b，Il6和Tnfa的mRNA表達降低，同時也會降低M1細胞的殺菌能力。Ak4的敲除（KO）在體內不影響骨髓細胞群，包括髓樣和淋巴樣細胞。Ak4的敲除（KO）亦不會影響BMDM的成熟以及M1和M2的極化。但是，在M1巨噬細胞中缺乏Ak4時，炎症基因的表達包括 Il1b、Il6、Tnfa、Nos2、Nox2 和 Hif1a表達下降。同樣， M1巨噬細胞的殺菌能力也會降低。因此，我們的研究顯示了將巨噬細胞的能量消耗與發炎連結的潛在機制。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:02:47Z (GMT). No. of bitstreams: 1 U0001-1007202115445400.pdf: 6054885 bytes, checksum: 5f5f39a3fe6b727a76c0293e1ab3bc70 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "Acknowledgments………………………………………….…………………………I Chinese abstract.……………………………………………….…………………..…III Abstract……………………………………………………………………………..…IV Contents….……………………………………………………………………………VI Tables of contents…………………………………………………………………….. XI Figures of contents…………………………………………….……………...……XII Supplementary Figures of contents……………………………………...…………XIV I. Introduction……………………………………………………………………... 1 1. Macrophages………………………………………………………………. 1 1.1 M1 Macrophage subset…...…………………………….………………. 2 1.2 M2 Macrophage subset…….………………………………………….... 3 1.3 Deactivated Macrophage…….……………………………………….... 3 2. Bone marrow-derived macrophages (BMDMs)….……………………….…4 3. Peritoneal macrophages (PMs) …...……………………………...……….…4 4. Homeostasis of macrophages………………………………………………5 5. Nitric oxide synthases in macrophages……………………………………5 6. Nitric oxide in macrophages………………………………………………6 7. Phagocytosis in macrophages………………………………………………7 8. Adenylate kinase……………………………………………………………7 9. Adenylate kinase 4………………………………………………………….8 10. HIF-1α in macrophage metabolism and functions………………………... 9 11. AMPK in macrophage metabolism and functions…...………………………9 12. Specific Aims……………………………………….………………………10 II. Materials and Methods…………………………………………………….12 1. Materials………………………………………………………………….12 2. Methods…………………………………………………………………...21 2.1 Isolation and development of bone marrow-derived macrophage……21 2.2 Isolation and polarization of peritoneal macrophages (PMs) …....…...22 2.3 Polarization of M1 and M2 subsets in vitro………………….……......22 2.4 Characterization of M1 and M2 macrophages by flow cytometry….... 23 2.5 Characterization of M1 and M2 macrophages by real-time PCR……...23 2.6 Characterization of M1 and M2 macrophages by Western blot analysis……………………………………………………………….24 2.7 Enzyme-linked immunosorbent assay (ELISA) for IL-1β, IL-6, and TNFα…………………………………………….…………………….... 25 2.8 Lentiviral production and transduction………………………...…...…26 2.9 siRNA transfection……………………………………….…...…...…26 2.10 Phagocytosis and killing assay………………………...……...…27 2.11 Statistical analysis…………………………………………............27 III. Results………………………………………………………………………29 1. Bone marrow (BM) cells were able to polarize into classical activation and alternative activation macrophages in vitro………………………………. 29 2. Nos2, Ccl2, Il1β, Il6, and Tnfα. were highly expressed in classically activated (M1) macrophage while Fizz1, Chil3, and Egr2 were highly expressed in alternatively activated (M2) macrophage………………….…………...... 30 3. Adenylate kinase 4 (Ak4) was high expressed in M1 macrophage compared to M0 and M2 macrophages………………………………………………30 4. Peritoneal macrophages (PMs) were isolated from the peritoneal cavity and able to polarize into M1 and M2 macrophages……....…………......……31 5. Nos2, Socs3, Cybb, Ccl2, and pro-inflammatory cytokine were expressed in classically activated PM1 macrophage while Fizz1, Chil3, Arg1, and Egr2 were highly expressed in alternatively activated PM2 macrophage…......…32 6. The iNOS, p-AMPK, and Hif1α were highly expressed in M1 macrophage compared to M0 and M2 macrophages…………………………………...33 7. Adenylate kinase 4 (Ak4) was highly expressed in PM1 macrophage compared to PM0 and PM2 macrophages…………………………………33 8. The gene expression of Hif1α, Tnfα, Il1β, Il6, and Nos2 were downregulated and Chil3 was upregulated in short hairpin RNA (shRNA) knockdown of Ak4 M1 macrophage……………………………….….………………......34 9. Expression of CD86 and CD206 were reduced and enhanced in Ak4 KD M1 macrophage, respectively.............…………………………………………35 10. Ak4 is critical for bactericidal ability in M1 Macrophage…………...……36 11. Ak4 siRNA knockdown classical activation macrophage showed a lower expression of pro-inflammatory cytokines……………….……………….36 12. There was no significant difference was observed in the bone marrow myeloid cell population between Ak4-/- mice and wild-type mice…………37 13. There was no significant difference was observed in the bone marrow lymphoid cell population between Ak4-/- mice and wild-type mice………37 14. Ak4 knockout does not affect BMDM development and M1 and M2 macrophages polarization. ……………………………………………….38 15. Ak4 regulates the expression of inflammation genes in M1 macrophage…39 16. Ak4 regulates AMPK activation and the expression of inflammation genes in M1 macrophage……………………………………………………………40 17. Bacteria clearance ability was reduced at MOI 5 in Ak4-/- M1 macrophage compared to wild-type M1 macrophage……………………………………40 IV. Discussion………………………………………………………………...… 43 V. Tables…………………………………………………………………...….... 48 VI. Figures………………………………………………………...……………53 VII. Supplementary Figures……………………………………………...……103 VIII. References…………………………………………………………...……111 IX.Appendix………………………………………………………………………...123" | |
| dc.language.iso | en | |
| dc.subject | α亞基 | zh_TW |
| dc.subject | 經典激活的巨噬細胞 | zh_TW |
| dc.subject | 交替激活的巨噬細胞 | zh_TW |
| dc.subject | 小髮夾RNA | zh_TW |
| dc.subject | 小分子干擾核糖核酸 | zh_TW |
| dc.subject | 敲低 | zh_TW |
| dc.subject | 敲除 | zh_TW |
| dc.subject | 腺苷酸激酶-4 | zh_TW |
| dc.subject | 缺氧誘導因子1 | zh_TW |
| dc.subject | knockout | en |
| dc.subject | Ak4 | en |
| dc.subject | Hif1α | en |
| dc.subject | classically activated macrophage | en |
| dc.subject | alternatively activated macrophages | en |
| dc.subject | shRNA | en |
| dc.subject | siRNA | en |
| dc.subject | knockdown | en |
| dc.title | 探討腺苷酸激酶-4於傳統及替代性活化巨噬細胞的功能 | zh_TW |
| dc.title | The Function of Adenylate Kinase 4 in Classically and Alternatively Activated Macrophages | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李建國(Hsin-Tsai Liu),徐立中(Chih-Yang Tseng) | |
| dc.subject.keyword | 腺苷酸激酶-4,缺氧誘導因子1,α亞基,經典激活的巨噬細胞,交替激活的巨噬細胞,小髮夾RNA,小分子干擾核糖核酸,敲低,敲除, | zh_TW |
| dc.subject.keyword | Ak4,Hif1α,classically activated macrophage,alternatively activated macrophages,shRNA,siRNA,knockdown,knockout, | en |
| dc.relation.page | 123 | |
| dc.identifier.doi | 10.6342/NTU202101378 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-08-03 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 免疫學研究所 | zh_TW |
| dc.date.embargo-lift | 2026-08-10 | - |
| 顯示於系所單位： | 免疫學研究所 | |
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