跳到主要內容

臺灣博碩士論文加值系統

(100.28.227.63) 您好!臺灣時間:2024/06/16 20:22
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:彭阿魯
研究生(外文):PONARULSELVAM SEKAR
論文名稱:探討P2X7受體在小膠質細胞之細胞功能與訊息傳遞
論文名稱(外文):Study the cellular functions and signaling pathways of P2X7 in microglia
指導教授:張淑芬張淑芬引用關係
指導教授(外文):Shwu-fen Chang
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:英文
論文頁數:110
中文關鍵詞:P2X7Mitochondriamitophagylysosomal biogenesisacidification
外文關鍵詞:P2X7Mitochondriamitophagylysosomal biogenesisacidification
相關次數:
  • 被引用被引用:0
  • 點閱點閱:118
  • 評分評分:
  • 下載下載:7
  • 收藏至我的研究室書目清單書目收藏:0
P2X7 is ubiquitously expressed in myeloid cells and regulates the pathophysiology of inflammatory diseases. Extracellular ATP and extracellular acidosis are danger signals at inflammatory sites and can modulate inflammation and immunity. Here, we investigated the coordinate actions of P2X7 and low pH in the cellular events in BV-2 microglial cells. We found that neutralized ATP (nATP) induces higher actions than acidic ATP (aATP) in increasing intracellular calcium and reactive oxygen species (ROS), decreasing intracellular potassium and causing cell death. Pretreatment of microglial cells with P2X7 antagonist A438079 can abrogate these effects. Notably, acidic extracellular pH can potentiate the actions of nATP. To mimic the actions of P2X7 activation, we co-treated BV-2 cells with potassium and calcium ionophores, and found that nigericin and ionomycin exerted the synergistic effects on the changes of above intracellular responses. Confocal microscopic image showed the induction of mitochondrial fission after nATP, nigericin and acidification treatments, and the enhancement of Drp-1 co-localization in mitochondria under nATP treatment in acidic condition. nATP can rapidly block mitochondrial ATP turnover and respiration capacity, which were partially mimicked by nigericin and ionomycin. Together, P2X7-mediated ionic fluxes and ROS production were attenuated by transient acidification, which by itself is not sufficient to induce any intracellular stress responses. However, sustained acidification can enhance ATP-induced cellular stress responses, and synergistically deteriorate the mitochondrial function.
The effect of P2X7 on mitophagy that involves in controlling cellular stress responses has not been investigated yet. In this study, we explored the role of P2X7 in mitochondrial and lysosomal functions in myeloid cells. In microglial cells and bone marrow-derived macrophages (BMDM), P2X7 agonist BzATP triggered AMPK activation and LC3II accumulation through ROS and CaMKKII pathways, and these effects were abolished by P2X7 antagonist A438079 and P2X7 knockout. Moreover, dramatic inhibition of mitochondrial oxygen consumption rate and decrease in mitochondrial mass following P2X7 activation were observed. AMPK inhibition by compound C or AMPK silencing reversed the P2X7 action in reduction of mitochondrial mass, induction of mitochondrial fission and mitophagy, but not in uncoupling of mitochondrial respiration. Interestingly, we found that P2X7 activation induced nuclear translocation of TFEB via an AMPK-dependent pathway and led to lysosomal biogenesis. Mimicking the actions of BzATP, nigericin also induced ROS-dependent AMPK activation, mitophagy, mitochondrial fission and respiratory inhibition. Longer exposure of BzATP induced cell death, and this effect was accompanied by the lysosomal instability and was inhibited by autophagic or cathepsin B inhibitors. Taken together, ROS- and CaMKK-dependent AMPK activation was involved in P2X7-mediated mitophagy, mitochondrial dynamics and lysosomal biogenesis in myeloid cells, which was followed by cytotoxicity partially resulting from mitophagy and cathepsin B activation.
P2X7 is ubiquitously expressed in myeloid cells and regulates the pathophysiology of inflammatory diseases. Extracellular ATP and extracellular acidosis are danger signals at inflammatory sites and can modulate inflammation and immunity. Here, we investigated the coordinate actions of P2X7 and low pH in the cellular events in BV-2 microglial cells. We found that neutralized ATP (nATP) induces higher actions than acidic ATP (aATP) in increasing intracellular calcium and reactive oxygen species (ROS), decreasing intracellular potassium and causing cell death. Pretreatment of microglial cells with P2X7 antagonist A438079 can abrogate these effects. Notably, acidic extracellular pH can potentiate the actions of nATP. To mimic the actions of P2X7 activation, we co-treated BV-2 cells with potassium and calcium ionophores, and found that nigericin and ionomycin exerted the synergistic effects on the changes of above intracellular responses. Confocal microscopic image showed the induction of mitochondrial fission after nATP, nigericin and acidification treatments, and the enhancement of Drp-1 co-localization in mitochondria under nATP treatment in acidic condition. nATP can rapidly block mitochondrial ATP turnover and respiration capacity, which were partially mimicked by nigericin and ionomycin. Together, P2X7-mediated ionic fluxes and ROS production were attenuated by transient acidification, which by itself is not sufficient to induce any intracellular stress responses. However, sustained acidification can enhance ATP-induced cellular stress responses, and synergistically deteriorate the mitochondrial function.
The effect of P2X7 on mitophagy that involves in controlling cellular stress responses has not been investigated yet. In this study, we explored the role of P2X7 in mitochondrial and lysosomal functions in myeloid cells. In microglial cells and bone marrow-derived macrophages (BMDM), P2X7 agonist BzATP triggered AMPK activation and LC3II accumulation through ROS and CaMKKII pathways, and these effects were abolished by P2X7 antagonist A438079 and P2X7 knockout. Moreover, dramatic inhibition of mitochondrial oxygen consumption rate and decrease in mitochondrial mass following P2X7 activation were observed. AMPK inhibition by compound C or AMPK silencing reversed the P2X7 action in reduction of mitochondrial mass, induction of mitochondrial fission and mitophagy, but not in uncoupling of mitochondrial respiration. Interestingly, we found that P2X7 activation induced nuclear translocation of TFEB via an AMPK-dependent pathway and led to lysosomal biogenesis. Mimicking the actions of BzATP, nigericin also induced ROS-dependent AMPK activation, mitophagy, mitochondrial fission and respiratory inhibition. Longer exposure of BzATP induced cell death, and this effect was accompanied by the lysosomal instability and was inhibited by autophagic or cathepsin B inhibitors. Taken together, ROS- and CaMKK-dependent AMPK activation was involved in P2X7-mediated mitophagy, mitochondrial dynamics and lysosomal biogenesis in myeloid cells, which was followed by cytotoxicity partially resulting from mitophagy and cathepsin B activation.
TABLE OF CONTENTS
ABBREVIATIONS--------------------------------------------------------------------------------------6
ABSTRACT-----------------------------------------------------------------------------------------------8
CHAPTER 1. INTRODUCTION--------------------------------------------------------------------10
1.1. Microglia functions in the central nervous system---------------------------------------------11
1.1.3 Role of microglia in neurodegenerative diseases ---------------------------------------------11
1.2. Autophagy------------------------------------------------------------------------------------------13
1.2.1. Specific degradation of mitochondria by mitophagy ---------------------------------------13
1.2.2. Mitochondrial dynamics – fusion and fission------------------------------------------------14
1.2.3. Mitophagy ----------------------------------------------------------------------------------------16
1.2.4. Lysosomal function – Biogenesis and digestion---------------------------------------------16
1.3. Purinoceptors--------------------------------------------------------------------------------------17
1.3.1. P2X7 receptors-----------------------------------------------------------------------------------18
1.3.2. P2X7 receptor signaling------------------------------------------------------------------------18
1.3.3. Role of P2X7 receptor in diseases-------------------------------------------------------------19
1.3.4. Role of P2X7 in mitochondrial dysfunction--------------------------------------------------21
1.4. AMPK signaling and cellular functions------------------------------------------------------22

1.5. Acidification – General implications---------------------------------------------------------22
CHAPTER 2. SPECIFIC AIMS-------------------------------------------------------------------24
CHAPTER 3. MATERIALS AND METHODS------------------------------------------------ 27
3.1. Animals and ethical statement------------------------------------------------------------------ 28
3.2. Reagents--------------------------------------------------------------------------------------------28
3.3 Cell culture -----------------------------------------------------------------------------------------29
3.4. Extracellular pH adjustment---------------------------------------------------------------------29
3.5. Preparation of nATP and aATP-----------------------------------------------------------------30
3.6. RNA interference---------------------------------------------------------------------------------30
3.7. Measurement of cytosolic and mitochondrial ROS production----------------------------31
3.8. MTT assay-----------------------------------------------------------------------------------------31
3.9. Annexin V/PI staining----------------------------------------------------------------------------31
3.10. Intracellular calcium and potassium measurements ----------------------------------------32
3.11. Measurement of mitochondrial oxygen consumption rate---------------------------------32
3.12. Measurement of mitochondrial membrane potential---------------------------------------33
3.13. Intracellular cathepsin B activity assay------------------------------------------------------34
3.14. Mitochondrial imaging-------------------------------------------------------------------------34
3.15. Subcellular fractionation and immunoblotting analysis------------------------------------35
3.16. Statistical analysis-------------------------------------------------------------------------------36
CHAPTER 4. RESULTS----------------------------------------------------------------------------37
Part I: Coordinate effects of P2X7 and extracellular acidification in microglial cells--38
4.1. nATP induces higher cellular responses than aATP------------------------------------------38
4.2. Sustained acidification enhances nATP-induced calcium increase and ROS
production ----------------------------------------------------------------------------------------39
4.3. ATP and sustained acidification on mitochondrial membrane potential and
mitochondrial dynamics-------------------------------------------------------------------------40
4.4. Both nATP and acidification reduce mitochondrial respiration----------------------------41
4.5. Nigericin and ionomycin synergistically causes mitochondrial toxicity as ATP--------42
Part II: AMPK-dependent and -independent actions of P2X7 in regulation of
mitochondrial and lysosomal functions in microglia-----------------------------------44
4.6. P2X7 induces Ca/CaMKK- and ROS-dependent AMPK activation in
microglia and macrophages -------------------------------------------------------------------44
4.7. P2X7 induces AMPK-dependent mitochondrial fission and mitophagy ---------------- 45
4.8. P2X7 inhibits mitochondrial respiration via a pathway independent of AMPK---------47
4.9. P2X7 induces lysosomal biogenesis via AMPK pathway----------------------------------47
4.10. P2X7 induces cathepsin B through lysosomal rupture and negatively
regulates TFEB----------------------------------------------------------------------------------48
CHAPTER 5. DISCUSSION AND CONCLUSION-----------------------------------------49
CHAPTER 6. REFERENCES--------------------------------------------------------------------58
CHAPTER 7. FIGURES AND LEGENDS----------------------------------------------------72
CHAPTER 9. SUMMARY FIGURE-----------------------------------------------------------103
CHAPTER 10. PUBLICATIONS---------------------------------------------------------------105
Chapter 11. APPENDIXES----------------------------------------------------------------------106
1.Ginhoux, F., Lim, S., Hoeffel, G., Low, D. & Huber, T. Origin and differentiation of microglia. Front Cell Neurosci 7, 45 (2013).

2.Allen, N.J. & Barres, B.A. Neuroscience: Glia - more than just brain glue. Nature 457, 675-677 (2009).

3.Jakel, S. & Dimou, L. Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation. Front Cell Neurosci 11, 24 (2017).

4.Salter, M.W. & Stevens, B. Microglia emerge as central players in brain disease. Nat Med 23, 1018-1027 (2017).

5.Varatharaj, A. & Galea, I. The blood-brain barrier in systemic inflammation. Brain Behav Immun 60, 1-12 (2017).

6.Perry, V.H., Nicoll, J.A. & Holmes, C. Microglia in neurodegenerative disease. Nat Rev Neurol 6, 193-201 (2010).

7.Kingwell, K. Neurodegenerative disease: Microglia in early disease stages. Nat Rev Neurol 8, 475 (2012).

8.Streit, W.J. & Kincaid-Colton, C.A. The brain''s immune system. Sci Am 273, 54-55, 58-61 (1995).

9.Griffin, W.S. et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 86, 7611-7615 (1989).

10.Xu, L., He, D. & Bai, Y. Microglia-Mediated Inflammation and Neurodegenerative Disease. Mol Neurobiol 53, 6709-6715 (2016).

11.Block, M.L., Zecca, L. & Hong, J.S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8, 57-69 (2007).

12.Weinstein, J.R., Koerner, I.P. & Moller, T. Microglia in ischemic brain injury. Future Neurol 5, 227-246 (2010).

13.Chen, Y. & Klionsky, D.J. The regulation of autophagy - unanswered questions. J Cell Sci 124, 161-170 (2011).

14.Choi, A.M., Ryter, S.W. & Levine, B. Autophagy in human health and disease. N Engl J Med 368, 651-662 (2013).

15.Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728-741 (2011).

16.Exner, N., Lutz, A.K., Haass, C. & Winklhofer, K.F. Mitochondrial dysfunction in Parkinson''s disease: molecular mechanisms and pathophysiological consequences. EMBO J 31, 3038-3062 (2012).

17.Kubli, D.A. & Gustafsson, A.B. Mitochondria and mitophagy: the yin and yang of cell death control. Circ Res 111, 1208-1221 (2012).

18.Ni, H.M., Williams, J.A. & Ding, W.X. Mitochondrial dynamics and mitochondrial quality control. Redox Biol 4, 6-13 (2015).

19.Dorn, G.W., 2nd & Kitsis, R.N. The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circ Res 116, 167-182 (2015).

20.Pickrell, A.M. & Youle, R.J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson''s disease. Neuron 85, 257-273 (2015).

21.Lionaki, E., Markaki, M., Palikaras, K. & Tavernarakis, N. Mitochondria, autophagy and age-associated neurodegenerative diseases: New insights into a complex interplay. Biochim Biophys Acta 1847, 1412-1423 (2015).

22.Chen, H. & Chan, D.C. Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum Mol Genet 18, R169-176 (2009).

23.Loson, O.C., Song, Z., Chen, H. & Chan, D.C. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24, 659-667 (2013).

24.Cribbs, J.T. & Strack, S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8, 939-944 (2007).

25.Jahani-Asl, A. & Slack, R.S. The phosphorylation state of Drp1 determines cell fate. EMBO Rep 8, 912-913 (2007).

26.Cereghetti, G.M. et al. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A 105, 15803-15808 (2008).

27.Cipolat, S., Martins de Brito, O., Dal Zilio, B. & Scorrano, L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A 101, 15927-15932 (2004).

28.Twig, G. et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27, 433-446 (2008).

29.Chen, Y. & Dorn, G.W., 2nd. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340, 471-475 (2013).

30.Twig, G. & Shirihai, O.S. The interplay between mitochondrial dynamics and mitophagy. Antioxid Redox Signal 14, 1939-1951 (2011).

31.Szklarczyk, R., Nooteboom, M. & Osiewacz, H.D. Control of mitochondrial integrity in ageing and disease. Philos Trans R Soc Lond B Biol Sci 369, 20130439 (2014).

32.Hroudova, J., Singh, N. & Fisar, Z. Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer''s disease. Biomed Res Int 2014, 175062 (2014).

33.Kudryavtseva, A.V. et al. Mitochondrial dysfunction and oxidative stress in aging and cancer. Oncotarget 7, 44879-44905 (2016).

34.Youle, R.J. & Narendra, D.P. Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12, 9-14 (2011).

35.Okatsu, K. et al. p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 15, 887-900 (2010).

36.Ashrafi, G. & Schwarz, T.L. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 20, 31-42 (2013).

37.Glick, D., Barth, S. & Macleod, K.F. Autophagy: cellular and molecular mechanisms. J Pathol 221, 3-12 (2010).

38.Burnstock, G. Purinergic nerves. Pharmacol Rev 24, 509-581 (1972).

39.Burnstock, G., Campbell, G., Satchell, D. & Smythe, A. Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut. Br J Pharmacol 40, 668-688 (1970).

40.Evans, R.J. Structural interpretation of P2X receptor mutagenesis studies on drug action. Br J Pharmacol 161, 961-971 (2010).

41.Jiang, L.H., Rassendren, F., Surprenant, A. & North, R.A. Identification of amino acid residues contributing to the ATP-binding site of a purinergic P2X receptor. J Biol Chem 275, 34190-34196 (2000).

42.Arulkumaran, N., Unwin, R.J. & Tam, F.W. A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin Investig Drugs 20, 897-915 (2011).

43.Burnstock, G. Historical review: ATP as a neurotransmitter. Trends Pharmacol Sci 27, 166-176 (2006).

44.Steinberg, T.H., Newman, A.S., Swanson, J.A. & Silverstein, S.C. ATP4- permeabilizes the plasma membrane of mouse macrophages to fluorescent dyes. J Biol Chem 262, 8884-8888 (1987).

45.Seeland, S. et al. ATP-induced cellular stress and mitochondrial toxicity in cells expressing purinergic P2X7 receptor. Pharmacol Res Perspect 3, e00123 (2015).

46.Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821-832 (2010).

47.Hwang, S.M. et al. P2X7 Receptor-mediated Membrane Blebbing in Salivary Epithelial Cells. Korean J Physiol Pharmacol 13, 175-179 (2009).

48.Bartlett, R., Yerbury, J.J. & Sluyter, R. P2X7 receptor activation induces reactive oxygen species formation and cell death in murine EOC13 microglia. Mediators Inflamm 2013, 271813 (2013).

49.Ferrari, D. et al. Mouse microglial cells express a plasma membrane pore gated by extracellular ATP. J Immunol 156, 1531-1539 (1996).

50.Coutinho-Silva, R. & Ojcius, D.M. Role of extracellular nucleotides in the immune response against intracellular bacteria and protozoan parasites. Microbes Infect 14, 1271-1277 (2012).

51.Skaper, S.D., Debetto, P. & Giusti, P. The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB J 24, 337-345 (2010).

52.Beaucage, K.L. et al. Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice. Purinergic Signal 10, 291-304 (2014).

53.Sperlagh, B. & Illes, P. P2X7 receptor: an emerging target in central nervous system diseases. Trends Pharmacol Sci 35, 537-547 (2014).

54.Garlick, P.B., Radda, G.K. & Seeley, P.J. Studies of acidosis in the ischaemic heart by phosphorus nuclear magnetic resonance. Biochem J 184, 547-554 (1979).

55.Nedergaard, M., Kraig, R.P., Tanabe, J. & Pulsinelli, W.A. Dynamics of interstitial and intracellular pH in evolving brain infarct. Am J Physiol 260, R581-588 (1991).

56.Giannuzzo, A. et al. Targeting of the P2X7 receptor in pancreatic cancer and stellate cells. Int J Cancer 139, 2540-2552 (2016).

57.Di Virgilio, F. & Adinolfi, E. Extracellular purines, purinergic receptors and tumor growth. Oncogene 36, 293-303 (2017).

58.Bhattacharya, A. & Biber, K. The microglial ATP-gated ion channel P2X7 as a CNS drug target. Glia 64, 1772-1787 (2016).

59.Bhattacharya, A. Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders. Front Pharmacol 9, 30 (2018).

60.Beamer, E., Fischer, W. & Engel, T. The ATP-Gated P2X7 Receptor As a Target for the Treatment of Drug-Resistant Epilepsy. Front Neurosci 11, 21 (2017).

61.Burnstock, G. Purinergic Mechanisms and Pain. Adv Pharmacol 75, 91-137 (2016).

62.McLarnon, J.G. Roles of purinergic P2X7 receptor in glioma and microglia in brain tumors. Cancer Lett 402, 93-99 (2017).

63.Naghavi, M. et al. pH Heterogeneity of human and rabbit atherosclerotic plaques; a new insight into detection of vulnerable plaque. Atherosclerosis 164, 27-35 (2002).

64.Farr, M., Garvey, K., Bold, A.M., Kendall, M.J. & Bacon, P.A. Significance of the hydrogen ion concentration in synovial fluid in rheumatoid arthritis. Clin Exp Rheumatol 3, 99-104 (1985).

65.Hunt, J.F. et al. Endogenous airway acidification. Implications for asthma pathophysiology. Am J Respir Crit Care Med 161, 694-699 (2000).

66.Roiniotis, J. et al. Hypoxia prolongs monocyte/macrophage survival and enhanced glycolysis is associated with their maturation under aerobic conditions. J Immunol 182, 7974-7981 (2009).

67.Tannahill, G.M. & O''Neill, L.A. The emerging role of metabolic regulation in the functioning of Toll-like receptors and the NOD-like receptor Nlrp3. FEBS Lett 585, 1568-1572 (2011).

68.Coakley, R.J., Taggart, C., McElvaney, N.G. & O''Neill, S.J. Cytosolic pH and the inflammatory microenvironment modulate cell death in human neutrophils after phagocytosis. Blood 100, 3383-3391 (2002).

69.Pliyev, B.K., Sumarokov, A.B., Buriachkovskaia, L.I. & Menshikov, M. Extracellular acidosis promotes neutrophil transdifferentiation to MHC class II-expressing cells. Cell Immunol 271, 214-218 (2011).

70.Cao, S. et al. Extracellular Acidification Acts as a Key Modulator of Neutrophil Apoptosis and Functions. PLoS One 10, e0137221 (2015).

71.Grabowski, J. et al. Tumor necrosis factor expression is ameliorated after exposure to an acidic environment. J Surg Res 173, 127-134 (2012).

72.Park, S.Y. & Kim, I.S. Identification of macrophage genes responsive to extracellular acidification. Inflamm Res 62, 399-406 (2013).

73.Matsuzaki, S. et al. Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells. Biochem Biophys Res Commun 413, 499-503 (2011).

74.Zhou, Q. & Bett, G.C. Regulation of the voltage-insensitive step of HERG activation by extracellular pH. Am J Physiol Heart Circ Physiol 298, H1710-1718 (2010).

75.Renner, N.A. et al. Transient acidification and subsequent proinflammatory cytokine stimulation of astrocytes induce distinct activation phenotypes. J Cell Physiol 228, 1284-1294 (2013).

76.Langfelder, A., Okonji, E., Deca, D., Wei, W.C. & Glitsch, M.D. Extracellular acidosis impairs P2Y receptor-mediated Ca(2+) signalling and migration of microglia. Cell Calcium 57, 247-256 (2015).

77.Oorni, K. et al. Acidification of the intimal fluid: the perfect storm for atherogenesis. J Lipid Res 56, 203-214 (2015).

78.Rukwied, R. et al. Potentiation of nociceptive responses to low pH injections in humans by prostaglandin E2. J Pain 8, 443-451 (2007).

79.Rajamaki, K. et al. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J Biol Chem 288, 13410-13419 (2013).

80.Cisneros-Mejorado, A. et al. Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage. J Cereb Blood Flow Metab 35, 843-850 (2015).

81.Cotrina, M.L. & Nedergaard, M. Physiological and pathological functions of P2X7 receptor in the spinal cord. Purinergic Signal 5, 223-232 (2009).

82.Di Virgilio, F., Dal Ben, D., Sarti, A.C., Giuliani, A.L. & Falzoni, S. The P2X7 Receptor in Infection and Inflammation. Immunity 47, 15-31 (2017).

83.Parvathenani, L.K. et al. P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer''s disease. J Biol Chem 278, 13309-13317 (2003).

84.Kumar, S., Mishra, A. & Krishnamurthy, S. Purinergic Antagonism Prevents Mitochondrial Dysfunction and Behavioral Deficits Associated with Dopaminergic Toxicity Induced by 6-OHDA in Rats. Neurochem Res 42, 3414-3430 (2017).

85.Schon, E.A. & Manfredi, G. Neuronal degeneration and mitochondrial dysfunction. J Clin Invest 111, 303-312 (2003).

86.Domise, M. & Vingtdeux, V. AMPK in Neurodegenerative Diseases. Exp Suppl 107, 153-177 (2016).

87.Garcia, D. & Shaw, R.J. AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Mol Cell 66, 789-800 (2017).

88.Toyama, E.Q. et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275-281 (2016).

89.Herzig, S. & Shaw, R.J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19, 121-135 (2018).

90.Carroll, B. & Dunlop, E.A. The lysosome: a crucial hub for AMPK and mTORC1 signalling. Biochem J 474, 1453-1466 (2017).

91.Hipolito, V.E.B., Ospina-Escobar, E. & Botelho, R.J. Lysosome remodelling and adaptation during phagocyte activation. Cell Microbiol 20 (2018).

92.Lin, S.C. & Hardie, D.G. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metab 27, 299-313 (2018).

93.Young, N.P. et al. AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes. Genes Dev 30, 535-552 (2016).

94.Kellum, J.A., Song, M. & Li, J. Science review: extracellular acidosis and the immune response: clinical and physiologic implications. Crit Care 8, 331-336 (2004).

95.Lardner, A. The effects of extracellular pH on immune function. J Leukoc Biol 69, 522-530 (2001).

96.Solle, M. et al. Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 276, 125-132 (2001).

97.Mohanraj, M., Sekar, P., Liou, H.H., Chang, S.F. & Lin, W.W. The Mycobacterial Adjuvant Analogue TDB Attenuates Neuroinflammation via Mincle-Independent PLC-gamma1/PKC/ERK Signaling and Microglial Polarization. Mol Neurobiol (2018).

98.Liao, Y.H. et al. HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation. J Leukoc Biol 93, 289-299 (2013).

99.Lin, Y.C., Huang, D.Y., Chu, C.L., Lin, Y.L. & Lin, W.W. The tyrosine kinase Syk differentially regulates Toll-like receptor signaling downstream of the adaptor molecules TRAF6 and TRAF3. Sci Signal 6, ra71 (2013).

100.Nishida, K. et al. Mitochondrial dysfunction is involved in P2X7 receptor-mediated neuronal cell death. J Neurochem 122, 1118-1128 (2012).

101.Mizushima, N. & Yoshimori, T. How to interpret LC3 immunoblotting. Autophagy 3, 542-545 (2007).

102.Pendergrass, W., Wolf, N. & Poot, M. Efficacy of MitoTracker Green and CMXrosamine to measure changes in mitochondrial membrane potentials in living cells and tissues. Cytometry A 61, 162-169 (2004).

103.de Castro, M.A., Bunt, G. & Wouters, F.S. Cathepsin B launches an apoptotic exit effort upon cell death-associated disruption of lysosomes. Cell Death Discov 2, 16012 (2016).

104.Qi, X. et al. Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection. J Exp Med 213, 2081-2097 (2016).

105.Diaz-Hernandez, J.I. et al. In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer''s disease through GSK3beta and secretases. Neurobiol Aging 33, 1816-1828 (2012).

106.McInnes, I.B., Cruwys, S., Bowers, K. & Braddock, M. Targeting the P2X7 receptor in rheumatoid arthritis: biological rationale for P2X7 antagonism. Clin Exp Rheumatol 32, 878-882 (2014).

107.Monif, M., Reid, C.A., Powell, K.L., Smart, M.L. & Williams, D.A. The P2X7 receptor drives microglial activation and proliferation: a trophic role for P2X7R pore. J Neurosci 29, 3781-3791 (2009).

108.Bianco, F. et al. A role for P2X7 in microglial proliferation. J Neurochem 99, 745-758 (2006).

109.Xiong, Z.G., Pignataro, G., Li, M., Chang, S.Y. & Simon, R.P. Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol 8, 25-32 (2008).

110.Damaghi, M., Wojtkowiak, J.W. & Gillies, R.J. pH sensing and regulation in cancer. Front Physiol 4, 370 (2013).

111.Liu, X., Ma, W., Surprenant, A. & Jiang, L.H. Identification of the amino acid residues in the extracellular domain of rat P2X(7) receptor involved in functional inhibition by acidic pH. Br J Pharmacol 156, 135-142 (2009).

112.Mackenzie, A.B., Young, M.T., Adinolfi, E. & Surprenant, A. Pseudoapoptosis induced by brief activation of ATP-gated P2X7 receptors. J Biol Chem 280, 33968-33976 (2005).

113.Noguchi, T. et al. Requirement of reactive oxygen species-dependent activation of ASK1-p38 MAPK pathway for extracellular ATP-induced apoptosis in macrophage. J Biol Chem 283, 7657-7665 (2008).

114.Eyo, U.B., Miner, S.A., Ahlers, K.E., Wu, L.J. & Dailey, M.E. P2X7 receptor activation regulates microglial cell death during oxygen-glucose deprivation. Neuropharmacology 73, 311-319 (2013).

115.Brough, D., Le Feuvre, R.A., Iwakura, Y. & Rothwell, N.J. Purinergic (P2X7) receptor activation of microglia induces cell death via an interleukin-1-independent mechanism. Mol Cell Neurosci 19, 272-280 (2002).

116.Ferrari, D. et al. ATP-mediated cytotoxicity in microglial cells. Neuropharmacology 36, 1295-1301 (1997).

117.Wann, J.G. et al. Neutrophils in acidotic haemodialysed patients have lower intracellular pH and inflamed state. Nephrol Dial Transplant 22, 2613-2622 (2007).

118.Faff, L. & Nolte, C. Extracellular acidification decreases the basal motility of cultured mouse microglia via the rearrangement of the actin cytoskeleton. Brain Res 853, 22-31 (2000).

119.Malayev, A. & Nelson, D.J. Extracellular pH modulates the Ca2+ current activated by depletion of intracellular Ca2+ stores in human macrophages. J Membr Biol 146, 101-111 (1995).

120.Wang, X. et al. Imaging ROS signaling in cells and animals. J Mol Med (Berl) 91, 917-927 (2013).

121.Robinson, K.M. et al. Selective fluorescent imaging of superoxide in vivo using ethidium-based probes. Proc Natl Acad Sci U S A 103, 15038-15043 (2006).

122.O''Rourke, B., Cortassa, S. & Aon, M.A. Mitochondrial ion channels: gatekeepers of life and death. Physiology (Bethesda) 20, 303-315 (2005).

123.Szabo, I. & Zoratti, M. Mitochondrial channels: ion fluxes and more. Physiol Rev 94, 519-608 (2014).

124.Adinolfi, E. et al. Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol Biol Cell 16, 3260-3272 (2005).

125.Li, X. et al. Acid-sensing ion channel 1a-mediated calcium influx regulates apoptosis of endplate chondrocytes in intervertebral discs. Expert Opin Ther Targets 18, 1-14 (2014).

126.Kostyuk, P., Potapenko, E., Siryk, I., Voitenko, N. & Kostyuk, E. Intracellular calcium homeostasis changes induced in rat spinal cord neurons by extracellular acidification. Neurochem Res 28, 1543-1547 (2003).

127.Metaxakis, A., Ploumi, C. & Tavernarakis, N. Autophagy in Age-Associated Neurodegeneration. Cells 7 (2018).

128.Zhang, J., Culp, M.L., Craver, J.G. & Darley-Usmar, V. Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson''s disease. J Neurochem 144, 691-709 (2018).

129.Sekar, P., Huang, D.Y., Chang, S.F. & Lin, W.W. Coordinate effects of P2X7 and extracellular acidification in microglial cells. Oncotarget 9, 12718-12731 (2018).

130.Fabbrizio, P., Amadio, S., Apolloni, S. & Volonte, C. P2X7 Receptor Activation Modulates Autophagy in SOD1-G93A Mouse Microglia. Front Cell Neurosci 11, 249 (2017).

131.Young, C.N. et al. A novel mechanism of autophagic cell death in dystrophic muscle regulated by P2RX7 receptor large-pore formation and HSP90. Autophagy 11, 113-130 (2015).

132.Biswas, D. et al. ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages. BMC Immunol 9, 35 (2008).

133.Das, S. et al. Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 305, G950-963 (2013).

134.Souza, C.O. et al. Extracellular ATP induces cell death in human intestinal epithelial cells. Biochim Biophys Acta 1820, 1867-1878 (2012).

135.Takenouchi, T. et al. The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells. J Immunol 182, 2051-2062 (2009).

136.Shah, S.Z.A., Zhao, D., Hussain, T. & Yang, L. Role of the AMPK pathway in promoting autophagic flux via modulating mitochondrial dynamics in neurodegenerative diseases: Insight into prion diseases. Ageing Res Rev 40, 51-63 (2017).

137.Matsuda, N. Phospho-ubiquitin: upending the PINK-Parkin-ubiquitin cascade. J Biochem 159, 379-385 (2016).

138.Wang, B. et al. AMPKalpha2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation. Circ Res 122, 712-729 (2018).

139.Narendra, D., Walker, J.E. & Youle, R. Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism. Cold Spring Harb Perspect Biol 4 (2012).

140.Sakamoto, A. et al. Eicosapentaenoic acid ameliorates palmitate-induced lipotoxicity via the AMP kinase/dynamin-related protein-1 signaling pathway in differentiated H9c2 myocytes. Exp Cell Res 351, 109-120 (2017).

141.Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429-1433 (2011).

142.Bian, S. et al. P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PLoS One 8, e60184 (2013).

143.da Silva, C.G., Jarzyna, R., Specht, A. & Kaczmarek, E. Extracellular nucleotides and adenosine independently activate AMP-activated protein kinase in endothelial cells: involvement of P2 receptors and adenosine transporters. Circ Res 98, e39-47 (2006).

144.Wu, C.A., Chao, Y., Shiah, S.G. & Lin, W.W. Nutrient deprivation induces the Warburg effect through ROS/AMPK-dependent activation of pyruvate dehydrogenase kinase. Biochim Biophys Acta 1833, 1147-1156 (2013).

145.Park, J. et al. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways. Neurosci Lett 584, 191-196 (2015).

146.Sundararaman, A., Amirtham, U. & Rangarajan, A. Calcium-Oxidant Signaling Network Regulates AMP-activated Protein Kinase (AMPK) Activation upon Matrix Deprivation. J Biol Chem 291, 14410-14429 (2016).

147.Mungai, P.T. et al. Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol Cell Biol 31, 3531-3545 (2011).

148.Vincent, E.E. et al. Differential effects of AMPK agonists on cell growth and metabolism. Oncogene 34, 3627-3639 (2015).

149.Berezhnov, A.V. et al. Intracellular pH Modulates Autophagy and Mitophagy. J Biol Chem 291, 8701-8708 (2016).

150.Huang, Y. et al. The AMP-Dependent Protein Kinase (AMPK) Activator A-769662 Causes Arterial Relaxation by Reducing Cytosolic Free Calcium Independently of an Increase in AMPK Phosphorylation. Front Pharmacol 8, 756 (2017).

151.Vlachaki Walker, J.M. et al. AMP-activated protein kinase (AMPK) activator A-769662 increases intracellular calcium and ATP release from astrocytes in an AMPK-independent manner. Diabetes Obes Metab 19, 997-1005 (2017).
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊