Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Signaling Pathways Controlling Microglia Chemotaxis

  • Fan, Yang (School of Pharmaceutical Science and Technology, Tianjin University) ;
  • Xie, Lirui (School of Pharmaceutical Science and Technology, Tianjin University) ;
  • Chung, Chang Y. (School of Pharmaceutical Science and Technology, Tianjin University)
  • Received : 2017.01.24
  • Accepted : 2017.03.07
  • Published : 2017.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Microglia are the primary resident immune cells of the central nervous system (CNS). They are the first line of defense of the brain's innate immune response against infection, injury, and diseases. Microglia respond to extracellular signals and engulf unwanted neuronal debris by phagocytosis, thereby maintaining normal cellular homeostasis in the CNS. Pathological stimuli such as neuronal injury induce transformation and activation of resting microglia with ramified morphology into a motile amoeboid form and activated microglia chemotax toward lesion site. This review outlines the current research on microglial activation and chemotaxis.

Keywords

References

  1. Barcia, C., Ros, C.M., Annese, V., Gomez, A., Ros-Bernal, F., Aguado- Llera, D., Martinez-Pagan, M.E., de Pablos, V., Fernandez-Villalba, E., and Herrero, M.T. (2012). IFN-gamma signaling, with the synergistic contribution of TNF-alpha, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease. Cell. Death Dis. 3, e379. https://doi.org/10.1038/cddis.2012.123
  2. Block, M.L. (2014). Neuroinflammation: modulating mighty microglia. Nat. Chem Biol. 10, 988-989. https://doi.org/10.1038/nchembio.1691
  3. Carnevale, K.A., and Cathcart, M.K. (2001). Calcium-independent phospholipase A(2) is required for human monocyte chemotaxis to monocyte chemoattractant protein 1. J. Immunol. 167, 3414-3421. https://doi.org/10.4049/jimmunol.167.6.3414
  4. Castellano, E., and Downward, J. (2010). Role of RAS in the regulation of PI 3-kinase. Curr. Top Microbiol. Immunol. 346, 143-169.
  5. Chen, L., Iijima, M., Tang, M., Landree, M.A., Huang, Y.E., Xiong, Y., Iglesias, P.A., and Devreotes, P.N. (2007). PLA2 and PI3K/PTEN pathways act in parallel to mediate chemotaxis. Dev. Cell 12, 603-614. https://doi.org/10.1016/j.devcel.2007.03.005
  6. Colton, C., and Wilcock, D.M. (2010). Assessing activation states in microglia. CNS Neurol. Disord. Drug Targets 9, 174-191. https://doi.org/10.2174/187152710791012053
  7. Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S., Littman, D.R., Dustin, M.L., and Gan, W.B. (2005). ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752-758. https://doi.org/10.1038/nn1472
  8. Delgado, M. (2003). Inhibition of interferon (IFN) gamma-induced Jak-STAT1 activation in microglia by vasoactive intestinal peptide: inhibitory effect on CD40, IFN-induced protein-10, and inducible nitric-oxide synthase expression. J. Biol. Chem. 278, 27620-27629. https://doi.org/10.1074/jbc.M303199200
  9. Dubyak, G.R., and el-Moatassim, C. (1993). Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides. Am. J. Physiol. 265, C577-606. https://doi.org/10.1152/ajpcell.1993.265.3.C577
  10. Gordon, S. (2003). Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23-35. https://doi.org/10.1038/nri978
  11. Haugh, J.M., Codazzi, F., Teruel, M., and Meyer, T. (2000). Spatial sensing in fibroblasts mediated by 3' phosphoinositides. J. Cell. Biol. 151, 1269-1280. https://doi.org/10.1083/jcb.151.6.1269
  12. Haynes, S.E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M.E., Gan, W.B., and Julius, D. (2006). The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat. Neurosci. 9, 1512-1519. https://doi.org/10.1038/nn1805
  13. Honda, S., Sasaki, Y., Ohsawa, K., Imai, Y., Nakamura, Y., Inoue, K., and Kohsaka, S. (2001). Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J. Neurosci. 21, 1975-1982. https://doi.org/10.1523/JNEUROSCI.21-06-01975.2001
  14. Inoue, K. (2002). Microglial activation by purines and pyrimidines. Glia 40, 156-163. https://doi.org/10.1002/glia.10150
  15. Irino, Y., Nakamura, Y., Inoue, K., Kohsaka, S., and Ohsawa, K. (2008). Akt activation is involved in P2Y12 receptor-mediated chemotaxis of microglia. J. Neurosci. Res. 86, 1511-1519. https://doi.org/10.1002/jnr.21610
  16. Ito, S., Kimura, K., Haneda, M., Ishida, Y., Sawada, M., and Isobe, K. (2007). Induction of matrix metalloproteinases (MMP3, MMP12 and MMP13) expression in the microglia by amyloid-beta stimulation via the PI3K/Akt pathway. Exp. Gerontol. 42, 532-537. https://doi.org/10.1016/j.exger.2006.11.012
  17. Kettenmann, H., and Verkhratsky, A. (2011). [Neuroglia--living nerve glue]. Fortschr. Neurol. Psychiatr 79, 588-597. https://doi.org/10.1055/s-0031-1281704
  18. Kim, W.K., Kan, Y., Ganea, D., Hart, R.P., Gozes, I., and Jonakait, G.M. (2000). Vasoactive intestinal peptide and pituitary adenylyl cyclase-activating polypeptide inhibit tumor necrosis factor-alpha production in injured spinal cord and in activated microglia via a cAMP-dependent pathway. J. Neurosci. 20, 3622-3630. https://doi.org/10.1523/JNEUROSCI.20-10-03622.2000
  19. Kreutzberg, G.W. (1996). Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312-318. https://doi.org/10.1016/0166-2236(96)10049-7
  20. Lee, S., and Chung, C.Y. (2009). Role of VASP phosphorylation for the regulation of microglia chemotaxis via the regulation of focal adhesion formation/maturation. Mol. Cell Neurosci. 42, 382-390. https://doi.org/10.1016/j.mcn.2009.08.010
  21. Lee, S.H., Schneider, C., Higdon, A.N., Darley-Usmar, V.M., and Chung, C.Y. (2011). Role of iPLA(2) in the regulation of Src trafficking and microglia chemotaxis. Traffic 12, 878-889. https://doi.org/10.1111/j.1600-0854.2011.01195.x
  22. Lee, S.H., Hollingsworth, R., Kwon, H.Y., Lee, N., and Chung, C.Y. (2012). beta-arrestin 2-dependent activation of ERK1/2 is required for ADP-induced paxillin phosphorylation at Ser(83) and microglia chemotaxis. Glia 60, 1366-1377. https://doi.org/10.1002/glia.22355
  23. Lee, S.H., Sud, N., Lee, N., Subramaniyam, S., and Chung, C.Y. (2016). Regulation of Integrin alpha6 Recycling by Calciumindependent Phospholipase A2 (iPLA2) to Promote Microglia Chemotaxis on Laminin. J. Biol. Chem. 291, 23645-23653. https://doi.org/10.1074/jbc.M116.732610
  24. Lu, D.Y., Tang, C.H., Yeh, W.L., Wong, K.L., Lin, C.P., Chen, Y.H., Lai, C.H., Chen, Y.F., Leung, Y.M., and Fu, W.M. (2009). SDF-1alpha upregulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NFkappaB- dependent pathway in microglia. Eur J. Pharmacol. 613, 146-154. https://doi.org/10.1016/j.ejphar.2009.03.001
  25. Mishra, R.S., Carnevale, K.A., and Cathcart, M.K. (2008). iPLA2beta: front and center in human monocyte chemotaxis to MCP-1. J. Exp. Med. 205, 347-359. https://doi.org/10.1084/jem.20071243
  26. Nasu-Tada, K., Koizumi, S., and Inoue, K. (2005). Involvement of beta1 integrin in microglial chemotaxis and proliferation on fibronectin: different regulations by ADP through PKA. Glia 52, 98-107. https://doi.org/10.1002/glia.20224
  27. Neary, J.T., Baker, L., Jorgensen, S.L., and Norenberg, M.D. (1994). Extracellular ATP induces stellation and increases glial fibrillary acidic protein content and DNA synthesis in primary astrocyte cultures. Acta Neuropathol. 87, 8-13. https://doi.org/10.1007/BF00386249
  28. Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318. https://doi.org/10.1126/science.1110647
  29. Ohsawa, K., Irino, Y., Nakamura, Y., Akazawa, C., Inoue, K., and Kohsaka, S. (2007). Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis. Glia 55, 604-616. https://doi.org/10.1002/glia.20489
  30. Parent, C.A., Blacklock, B.J., Froehlich, W.M., Murphy, D.B., and Devreotes, P.N. (1998). G protein signaling events are activated at the leading edge of chemotactic cells. Cell 95, 81-91. https://doi.org/10.1016/S0092-8674(00)81784-5
  31. Prinz, M., and Priller, J. (2014). Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300-312. https://doi.org/10.1038/nrn3722
  32. Rickert, P., Weiner, O.D., Wang, F., Bourne, H.R., and Servant, G. (2000). Leukocytes navigate by compass: roles of PI3Kgamma and its lipid products. Trends Cell Biol. 10, 466-473. https://doi.org/10.1016/S0962-8924(00)01841-9
  33. Sasaki, A.T., and Firtel, R.A. (2006). Regulation of chemotaxis by the orchestrated activation of Ras, PI3K, and TOR. Eur. J. Cell Biol. 85, 873-895. https://doi.org/10.1016/j.ejcb.2006.04.007
  34. Sasaki, Y., Hoshi, M., Akazawa, C., Nakamura, Y., Tsuzuki, H., Inoue, K., and Kohsaka, S. (2003). Selective expression of Gi/o-coupled ATP receptor P2Y12 in microglia in rat brain. Glia 44, 242-250. https://doi.org/10.1002/glia.10293
  35. Shankar, H., Garcia, A., Prabhakar, J., Kim, S., and Kunapuli, S.P. (2006). P2Y12 receptor-mediated potentiation of thrombin-induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation. J. Thromb. Haemost. 4, 638-647. https://doi.org/10.1111/j.1538-7836.2006.01789.x
  36. Stence, N., Waite, M., and Dailey, M.E. (2001). Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33, 256-266. https://doi.org/10.1002/1098-1136(200103)33:3<256::AID-GLIA1024>3.0.CO;2-J
  37. Streit, W.J. (2002). Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40, 133-139. https://doi.org/10.1002/glia.10154
  38. Streit, W.J., Graeber, M.B., and Kreutzberg, G.W. (1988). Functional plasticity of microglia: a review. Glia 1, 301-307. https://doi.org/10.1002/glia.440010502
  39. Stuart, L.M., Bell, S.A., Stewart, C.R., Silver, J.M., Richard, J., Goss, J.L., Tseng, A.A., Zhang, A., El Khoury, J.B., and Moore, K.J. (2007). CD36 signals to the actin cytoskeleton and regulates microglial migration via a p130Cas complex. J. Biol. Chem. 282, 27392-27401. https://doi.org/10.1074/jbc.M702887200
  40. Suzumura, A. (2013). [Microglia in pathophysiology of neuroimmunological disorders]. Nihon. Rinsho. 71, 801-806.
  41. Swiatkowski, P., Murugan, M., Eyo, U.B., Wang, Y., Rangaraju, S., Oh, S.B., and Wu, L.J. (2016). Activation of microglial P2Y12 receptor is required for outward potassium currents in response to neuronal injury. Neuroscience 318, 22-33. https://doi.org/10.1016/j.neuroscience.2016.01.008
  42. Tatsumi, E., Yamanaka, H., Kobayashi, K., Yagi, H., Sakagami, M., and Noguchi, K. (2015). RhoA/ROCK pathway mediates p38 MAPK activation and morphological changes downstream of P2Y12/13 receptors in spinal microglia in neuropathic pain. Glia 63, 216-228. https://doi.org/10.1002/glia.22745
  43. Town, T., Nikolic, V., and Tan, J. (2005). The microglial "activation" continuum: from innate to adaptive responses. J. Neuroinflammation 2, 24. https://doi.org/10.1186/1742-2094-2-24
  44. van Haastert, P.J., Keizer-Gunnink, I., and Kortholt, A. (2007). Essential role of PI3-kinase and phospholipase A2 in Dictyostelium discoideum chemotaxis. J. Cell Biol. 177, 809-816. https://doi.org/10.1083/jcb.200701134
  45. Wang, F., Herzmark, P., Weiner, O.D., Srinivasan, S., Servant, G., and Bourne, H.R. (2002). Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils. Nat. Cell Biol. 4, 513-518. https://doi.org/10.1038/ncb810
  46. Wang, Y.P., Wu, Y., Li, L.Y., Zheng, J., Liu, R.G., Zhou, J.P., Yuan, S.Y., Shang, Y., and Yao, S.L. (2011). Aspirin-triggered lipoxin A4 attenuates LPS-induced pro-inflammatory responses by inhibiting activation of NF-kappaB and MAPKs in BV-2 microglial cells. J. Neuroinflammation 8, 95. https://doi.org/10.1186/1742-2094-8-95
  47. Weiner, O.D., Neilsen, P.O., Prestwich, G.D., Kirschner, M.W., Cantley, L.C., and Bourne, H.R. (2002). A PtdInsP(3)- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity. Nat. Cell Biol. 4, 509-513. https://doi.org/10.1038/ncb811
  48. Zhang, X., Qin, J., Zou, J., Lv, Z., Tan, B., Shi, J., Zhao, Y., Ren, H., Liu, M., Qian, M., et al. (2016). Extracellular ADP facilitates monocyte recruitment in bacterial infection via ERK signaling. Cell Mol. Immunol. [Epub ahead of print]

Cited by

  1. Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy vol.11, pp.1662-453X, 2017, https://doi.org/10.3389/fnins.2017.00680
  2. Differential Regulation of Adhesion and Phagocytosis of Resting and Activated Microglia by Dopamine vol.12, pp.1662-5102, 2018, https://doi.org/10.3389/fncel.2018.00309
  3. Inflammation-induced iron transport and metabolism by brain microglia vol.293, pp.20, 2018, https://doi.org/10.1074/jbc.RA118.001949
  4. Autotaxin–Lysophosphatidic Acid Signaling in Alzheimer’s Disease vol.19, pp.7, 2018, https://doi.org/10.3390/ijms19071827
  5. Acute Neuroinflammatory Response in the Substantia Nigra Pars Compacta of Rats after a Local Injection of Lipopolysaccharide vol.2018, pp.2314-7156, 2018, https://doi.org/10.1155/2018/1838921
  6. Lysophosphatidic acid via LPA-receptor 5/protein kinase D-dependent pathways induces a motile and pro-inflammatory microglial phenotype vol.14, pp.None, 2017, https://doi.org/10.1186/s12974-017-1024-1
  7. Blockade of the Sigma-1 Receptor Relieves Cognitive and Emotional Impairments Associated to Chronic Osteoarthritis Pain vol.10, pp.None, 2017, https://doi.org/10.3389/fphar.2019.00468
  8. Different Approaches to Modulation of Microglia Phenotypes After Spinal Cord Injury vol.13, pp.None, 2019, https://doi.org/10.3389/fnsys.2019.00037
  9. Involvement of RhoA/ROCK Signaling in Aβ-Induced Chemotaxis, Cytotoxicity and Inflammatory Response of Microglial BV2 Cells vol.39, pp.5, 2017, https://doi.org/10.1007/s10571-019-00668-6
  10. Fabrication and Characterization of a Protein Composite Conduit for Neural Regeneration vol.2, pp.10, 2017, https://doi.org/10.1021/acsabm.9b00498
  11. Risks of progression of cerebrovascular pathology associated with the activity of the brain purinergic system vol.120, pp.10, 2017, https://doi.org/10.17116/jnevro2020120101118
  12. Recent Advancements in Engineering Strategies for Manipulating Neural Stem Cell Behavior vol.1, pp.2, 2017, https://doi.org/10.1007/s43152-020-00003-y
  13. High-resolution and differential analysis of rat microglial markers in traumatic brain injury: conventional flow cytometric and bioinformatics analysis vol.10, pp.None, 2020, https://doi.org/10.1038/s41598-020-68770-0
  14. Moesin is involved in microglial activation accompanying morphological changes and reorganization of the actin cytoskeleton vol.70, pp.1, 2017, https://doi.org/10.1186/s12576-020-00779-6
  15. Inhibitors of Src Family Kinases, Inducible Nitric Oxide Synthase, and NADPH Oxidase as Potential CNS Drug Targets for Neurological Diseases vol.35, pp.1, 2017, https://doi.org/10.1007/s40263-020-00787-5
  16. Sphingosine-1-phosphate induces migration of microglial cells via activation of volume-sensitive anion channels, ATP secretion and activation of purinergic receptors vol.1868, pp.2, 2021, https://doi.org/10.1016/j.bbamcr.2020.118915
  17. Microglia and Neuroinflammation: What Place for P2RY12? vol.22, pp.4, 2017, https://doi.org/10.3390/ijms22041636
  18. Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model vol.15, pp.None, 2017, https://doi.org/10.3389/fncel.2021.772868
  19. Alternative Targets to Fight Alzheimer’s Disease: Focus on Astrocytes vol.11, pp.4, 2017, https://doi.org/10.3390/biom11040600
  20. Anti-Neuroinflammatory Effects and Mechanism of Action of Fructus ligustri lucidi Extract in BV2 Microglia vol.10, pp.4, 2021, https://doi.org/10.3390/plants10040688
  21. Microglial remodeling of actin network by Tau oligomers, via G protein‐coupled purinergic receptor, P2Y12R‐driven chemotaxis vol.22, pp.5, 2021, https://doi.org/10.1111/tra.12784
  22. Functional Role of Non-Muscle Myosin II in Microglia: An Updated Review vol.22, pp.13, 2017, https://doi.org/10.3390/ijms22136687
  23. Gα13 Contributes to LPS-Induced Morphological Alterations and Affects Migration of Microglia vol.58, pp.12, 2021, https://doi.org/10.1007/s12035-021-02553-0
  24. Quantitative modeling of regular retinal microglia distribution vol.11, pp.1, 2017, https://doi.org/10.1038/s41598-021-01820-3
  25. The BET inhibitor attenuates the inflammatory response and cell migration in human microglial HMC3 cell line vol.11, pp.1, 2021, https://doi.org/10.1038/s41598-021-87828-1
  26. Phosphoinositides signaling modulates microglial actin remodeling and phagocytosis in Alzheimer’s disease vol.19, pp.1, 2017, https://doi.org/10.1186/s12964-021-00715-0
  27. Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress vol.11, pp.1, 2017, https://doi.org/10.3390/antiox11010061