Skip to main content

Advertisement

Log in

Brain Microglia and Microglial Markers

  • Published:
Neuroscience and Behavioral Physiology Aims and scope Submit manuscript

Recent years have seen a continuing increase in interest in various aspects of the organization and functioning of microglia. However, data on contemporary immunocytochemical methods for detecting microglia are ambiguous and need to be made systematic. Attention in the present review is focused on microglial markers – proteins (Iba-1, CD11b, CD68, HLA-DR, and others) expressed by microgliocytes in normal conditions and on activation evoked by harmful factors. Characterization of markers and immunocytochemical microglial labeling methods is combined with analysis of reports on the origin and structural organization of microgliocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. V. K. Beletskii, A Method for Microscopic Studies of the Nervous System, Krest’yanskaya Gazeta, Moscow (1939).

    Google Scholar 

  2. V. K. Beletskii, “Neurology in health and disease,” in: A Handbook of Pathological Anatomy in Several Volumes, Medical Literature Press, Moscow (1963), Vol. II, pp. 55–82.

  3. P. N. Ermokhin, Histopathology of the Central Nervous System: An Atlas of Photomicrographs, Meditsina, Moscow (1969).

    Google Scholar 

  4. O. V. Kirik, O. S. Alekseeva, A. N. Moskvin, and D. E. Korzhevskii, “Effects of hyperbaric oxygenation on the state of the subependymal microglia of the brain in rats,” Zh. Evolyuts. Biokhim., 50, No. 4, 312–314 (2014).

    CAS  Google Scholar 

  5. O. V. Kirik, E. G. Sukhorukova, O. S. Alekseeva, and D. E. Korzhevskii, “Subependymal microgliocytes of the III ventricle of the brain,” Morfologiya, 145, No. 3, 67–69 (2014).

    CAS  Google Scholar 

  6. O. V. Kirik, E. G. Sukhorukova, and D. E. Korzhevskii, “Calciumbinding protein Iba-1/AIF-1 in brain cells in the rat,” Morfologiya, 137, No. 2, 5–8 (2010).

    CAS  Google Scholar 

  7. D. E. Korzhevskii, “The tissue organization and development of the vascular plexus of the brain in humans,” Morfologiya, 113, No. 2, 105–114 (1998).

    CAS  Google Scholar 

  8. D. E. Korzhevskii, “Macrophages in the vascular plexus of the telencephalon in the human brain,” Morfologiya, 119, No. 1, 20–23 (2001).

    CAS  Google Scholar 

  9. D. E. Korzhevskii, O. V. Kirik, E. G. Sukhorukova, and T. D. Vlasov, “Structural organization of microgliocytes in the striatum after transient focal ischemia,” Morfologiya, 141, No. 2, 19–24 (2012).

    Google Scholar 

  10. D. E. Korzhevskii, O. V. Kirik, E. G. Sukhorukova, et al., “Studies of the spatial organization of astrocytes in the brain using confocal laser microscopy,” Morfologiya, 135, No. 3, 76–79 (2009).

    CAS  Google Scholar 

  11. D. E. Korzhevskii, O. V. Kirik, E. G. Sukhorukova, and M. A. Syrtsova, “Microglia in the substantia nigra of the brain in humans,” Med. Akad. Zh., 14, No. 4, 68–72 (2014).

    Google Scholar 

  12. D. E. Korzhevskii, M. V. Lentsman, O. V. Kirik, and V. A. Otellin, “Morphological types of activated microglia in the hippocampus seen after transient general cerebral ischemia,” Morfologiya, 142, No. 5, 30–33 (2012).

    CAS  Google Scholar 

  13. D. E. Korzhevskii, V. A. Otellin, A. A. Neokesariiskii, and N. G. Pavlova, “Structural organization of the forming human placenta,” Morfologiya, 128, No. 6, 60–62 (2005).

    CAS  Google Scholar 

  14. D. E. Korzhevskii, E. G. Sukhorukova E. G. Gilerovich, et al., “Advantages and disadvantages of zinc-ethanol-formaldehyde as a fixative for immunohistochemical studies and confocal laser microscopy,” Morfologiya, 143, No. 2, 81–85 (2013).

    CAS  Google Scholar 

  15. D. E. Korzhevskii, E. G. Sukhorukova E. G., and O. V. Kirik, “Use of immunocytochemical markers to detect activated microglia and macrophages in the brain,” in: Current Questions in Functional Interhemisphere Asymmetry and Neuroplasticity: Proc. All-Russ. Conf., Nauchnyi Mir, Moscow (2008), pp. 588–590.

  16. I. V. Manzhulo, Neuroglial Interactions in the Mechanisms of Development of Pain and Therapeutic Analgesia in Rats: Auth. Abstr. Mast. Thesis in Biol. Sci., Vladivostok (2013).

  17. V. A. Otellin and D. E. Korzhevskii, “Formation and structural organization of the barrier at the outer surface of the brain,” Morfologiya, 122, No. 6, 14–18 (2002).

    CAS  Google Scholar 

  18. E. G. Sukhorukova, M. S. Zakhryapin, N. N. Anichkov, and D. E. Korzhevskii, “Detection of microglia in brain preparations stored for prolonged periods in formalin solution,” Morfologiya, 142, No. 5, 32–35 (2012).

    Google Scholar 

  19. E. G. Sukhorukova, O. V. Kirik, and D. E. Korzhevskii, “Use of an immunohistochemical method to detect brain microglia in paraffin sections,” Byull. Eksperim. Biol., 149, No. 6, 709–712 (2010).

    Article  Google Scholar 

  20. L. I. Khozhai and V. A. Otellin, “Reactive changes in microglia in the rat neocortex and hippocampus after exposure to acute perinatal hypoxia,” Morfologiya, 143, No. 1, 23–27 (2013).

    CAS  Google Scholar 

  21. F. Alliott and I. Godin, “Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain,” Brain Res. Dev. Brain Res., 117, No. 2, 145–152 (1999).

    Article  Google Scholar 

  22. D. R. Beers, J. S. Henkel, Q. Xiao, et al., “Wild-type microglia extend survival in PU1 knockout mice with familial amyotrophic lateral sclerosis,” Proc. Natl. Acad. Sci. USA, 103, 16021–16026.

  23. L. Benimetskaya, J. D. Loike, Z. Khaled, et al., “Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein,” Nat. Med., 3, No. 4, 414–420 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. D. Boche, V. H. Perry, and J. A. Nicoll, “Review: activation patterns of microglia and their identification in the human brain,” Neuropathol. Appl. Neurobiol., 39, 3–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. J. G. Damoiseaux, E. A. Dopp, W. Calame, et al., “Rat macrophage lysosomal membrane antigen recognized by monoclonal antibody ED1,” Immunology, 83, 140–147 (1994).

    PubMed Central  CAS  PubMed  Google Scholar 

  26. M. H. Deininger, R. Meyermann, and H. J. Schluesener, “The allograft inflammatory factor-1 family of proteins,” FEBS Lett., 514, 115–121 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. C. D. Dijkstra, E. A. Dopp, P. Joling, and G. Kraal, “The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3,” Immunology, 54, 589–599 (1985).

    PubMed Central  CAS  PubMed  Google Scholar 

  28. C. D. Dijkstra, E. A. Dopp, T. K. Van der Burg, and J. G. Damoiseaux, “Monoclonal antibodies against rat macrophages,” J. Immunol. Meth., 174, 21–23 (1994).

    Article  CAS  Google Scholar 

  29. S. G. Elner, V. M. Elner, J. C. Nielsen, et al., “CD68 antigen expression by human retinal pigment epithelial cells,” Exp. Eye Res., 55, No. 1, 21–28 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. G. P. Fadini, R. Cappellari, M. Mazzucato, et al., “Monocyte-mac rophage polarization balance in pre-diabetic individuals,” Acta Diabetol., 50, No. 6, 977–982 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. B. Falini, L. Flenghi, S. Pileri, et al., “PG-M1: a new monoclonal anti body direct against a fixative-resistant epitope on the macrophage-restricted form of the CD68 molecule,” Am. J. Pathol., 142, No. 5, 1359–1372 (1993).

    PubMed Central  CAS  PubMed  Google Scholar 

  32. A. Flugel, M. Bradi, G. W. Kreutzberg, and M. B. Graeber, “Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy,” J. Neurosci. Res., 66, No. 1, 74–82 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. F. Ginhoux, M. Greater, M. Leboeuf, et al., “Fate mapping analysis reveals that adult microglia derive from primitive macrophages,” Science, 330, 841–845 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. M. B. Graeber and W. J. Streit, “Microglia: biology and pathology,” Acta Neuropathol., 119, 89–105 (2010).

    Article  PubMed  Google Scholar 

  35. M. Greater and M. Merad, “Regulation of microglia development and homeostasis,” Glia, 61, 121–127 (2013).

    Article  Google Scholar 

  36. G. J. Harry and A. D. Kratt, “Microglia in the developing brain: a potential target with lifetime effects,” Neurotoxicology, 33, 191–206 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  37. C. L. Holness and D. L. Simmons, “Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins,” Blood, 81, 1607–1613 (1993).

    CAS  PubMed  Google Scholar 

  38. R. J. Horvath, E. A. Romero-Sandoval, and J. A. De Leo, “Inhibition of microglial P2X4 receptor attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2,” Pain, 150, No. 3, 401–413 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Y. Imai, I. Ibata, D. Ito, et al., “A novel gene Iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage,” Biochem. Biophys. Res. Commun., 224, 855–862 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Y. Imai and S. Kohsaka, “Intracellular signaling in M-CSF-induced microglia activation: role of Iba1,” Glia, 40, 164–174 (2002).

    Article  PubMed  Google Scholar 

  41. D. Ito, Y. Imai, K. Ohsawa, et al., “Microglia-specific localization of a novel calcium binding protein, Iba1,” Brain Res. Mol. Brain Res., 57, 1–9, (1998).

    Article  CAS  PubMed  Google Scholar 

  42. C. Kaur and E.-A. Ling, “Increased expression of transferrin receptors and iron in ameboid microglial cells in postnatal rats following an exposure to hypoxia,” Neurosci. Lett., 262, 183–186 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. C. Kaur, G. Rathnasamy, and E.-A. Ling, “Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina,” J. Neuroim. Pharmacol., 8, 66–78 (2013).

    Article  Google Scholar 

  44. K. Kawai, N. H. Tsuno, M. Matsuhashi, et al., “CD11b-mediated migratory property of peripheral blood B cell,” J. Allergy Clin. Immunol., 116, No. 1, 192–197 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. C. Kohler, “Allograft inflammatory factor-1/Ionized calcium binding adapter molecule 1 is specifically expressed by most subpopulations of macrophages and spermatids in testis,” Cell Tissue Res., 33, 291–302 (2007).

    Article  Google Scholar 

  46. G. W. Kreutzberg, “Microglia: a sensor for pathological events in the CNS,” Trends Neurosci., 19, No. 8, 312–318 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. R. Ladeby, M. Wirenfeldt, D. Garcia-Ovejero, et al., “Microglial cell population dynamics in the injured adult central nervous system,” Brain Res. Brain Res. Rev., 48, No. 2, 196–206 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. E.-A. Ling, C. Kaur, and J. Lu, “Origin, nature and some functional considerations of intraventricular macrophages, with special reference to the epiplexus cells,” Microsc. Res. Tech., 41, No. 1, 235–342 (1998).

    Article  Google Scholar 

  49. M. MacPherson, H. S. Lek, A. Prescott, and S. C. Fagerholm, “A systemic lupus erythematosus-associated R77H substitution in the CD11b chain of the Mac-1 integrin compromises leukocyte adhesion and phagocytosis,” J. Biol. Chem., 286, 17,303–17,310 (2011).

    Article  CAS  Google Scholar 

  50. S. A. Marshall, J. A. McClain, M. L. Kelso, et al., “Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: The importance of microglia phenotype,” Neurobiol. Dis., 54, 239–251 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. S. M. McKay, D. J. Brooks, P. Hu, and E. M. McLachlan, “Distinct types of microglial activation in white and grey matter of rat lumbosacral cord after mid-thoracic spinal transection,” J. Neuropathol. Exp. Neurol., 66, 698–710 (2007).

    Article  PubMed  Google Scholar 

  52. T. Morioka, A. N. Kalehua, and W. J. Streit, “Progressive expression of immunomolecules on microglial cells in rat dorsal hippocampus following transient forebrain ischemia,” Acta Neuropathol., 83, No. 2, 149–157 (1992).

    Article  CAS  PubMed  Google Scholar 

  53. H. P. Ng, S. C. Chiang, Y. Chi, and S. T. Lee, “Identification of macrosialin (CD68) on the surface of host macrophages as the receptor for the intercellular adhesive molecule (ICAM-L) of Leishmania amazonensis,” Int. J. Parasitol., 39, 1539–1550 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. K. Osawa, Y. Imai, H. Kanazawa, et al., “Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia,” J. Cell Sci., 133, 3073–3084 (2000).

    Google Scholar 

  55. K. Osawa, Y. Imai, Y. Sasaki, and S. Kohsaka, “Microglia/macrophages-specific protein Iba1 binds to fimbrin and enhances its actin-bundling activity,” J. Neurochem., 88, 844–856 (2004).

    Article  Google Scholar 

  56. G. D. Ross, “Role of the lectin domain of Mac-1/CR3 (CD11b/ CD18) in regulating intercellular adhesion,” Immunol. Res, 25, No. 3, 219–227 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. G. D. Ross and V. Vetvicka, “CR3 (CD11b, CD18): a phagocyte and NK cell membrane receptor with multiple ligand specificities and functions,” Clin. Exp. Immunol., 92, 181–184 (1993).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Y. Sasaki, K. Ohsawa, H. Kanazawa, et al., “Iba1 is an actin-crosslinking protein in macrophage/microglia,” Biochem. Biophys. Res. Commun., 286, 292–297 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. A. Schuitemaker, T. F. Van der Doef, R. Boellard, et al., “Microglia activation in healthy aging,” Neurobiol. Aging, 33, 1067–1072 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. C. M. Shikuma, L. M. Gangcuangco, D. A. Killebrew, et al., “The role of HIV and monocytes/macrophages in adipose tissue biology,” J. Acquir. Imm. Defic. Syndr., 65, No. 2, 151–159 (2014).

    Article  CAS  Google Scholar 

  61. Y. J. Shin, J. M. Park, J. M. Cho, et al., “Induction of vascular endothelial growth factor receptor-3 expression in perivascular cells of the ischemic core following focal cerebral ischemia in rats,” Acta Histochem., 115, No. 2, 170–177(2013).

    Article  CAS  PubMed  Google Scholar 

  62. C. Smith, S. M. Gentleman, P. D. Leclerq, et al., “The inflammatory response in humans after traumatic brain injury,” Neuropathol. Appl. Neurobiol., 39, 654–666 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. C. Sobin, M. G. Montoya, N. Parisi, et al., “Microglial disruption in young mice with early chronic lead exposure,” Toxicol. Lett., 220, 44–52 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. L. Song, C. Lee, and C. Schindler, “Deletion of the murine scavenger receptor CD68,” J. Lipid Res., 52, 1542–1550 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. W. J. Streit, N. W. Sammons, A. J. Kuhns, and D. L. Sparks, “Dystrophic microglia in the aging human brain,” Glia, 45, 208–212 (2004).

    Article  PubMed  Google Scholar 

  66. K. Suzuki, G. Sugihara, Y. Ouchi, et al., “Microglial activation in young adults with autism spectrum disorder,” JAMA Psychiatry, 70, 49–58 (2013).

    Article  PubMed  Google Scholar 

  67. R. Todd, “The continuing saga of complement receptor type 3 (CR3),” J. Clin. Invest., 98, No. 1, 1–2 (1996).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. M. Tremblay, B. Stevens, A. Sierra, et al., “The role of microglia in the healthy brain,” J. Neurosci., 31, 16,064–16,069 (2011).

    Article  CAS  Google Scholar 

  69. M. M. Varnum and T. Ikezu, “The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain,” Arch. Immunol. Ther. Exp., 60, 251–266 (2012).

    Article  CAS  Google Scholar 

  70. H. Wake, A. J. Moorhouse, S. Jinno, et al., “Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals,” J. Neurosci., 29, 3974–3980 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. M. Wojtera, T. Sobow, I. Kłoszewska, et al., “Expression of immunohistochemical markers on microglia in Creutzfeldt-Jakob disease and Alzheimer’s disease: morphometric study and review of the literature,” Folia Neuropathol., 50, No. 1, 74–84 (2012).

    CAS  PubMed  Google Scholar 

  72. M. Yamada, K. Ohsawa, Y. Imai, et al., “x-Ray structure of the microglia/ macrophage-specific protein Iba1 from human and mouse demonstrate novel molecular conformation change induced by calcium binding,” J. Mol. Biol., 364, 449–457 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. M.-H. Yi, E. Zhang, J. W. Kang, et al., “Expression of CD200 in alternative activation of microglia following an excitotoxic lesion in the mouse hippocampus,” Brain Res., 1481, 90–96 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D. E. Korzhevskii.

Additional information

Translated from Morfologiya, Vol. 147, No. 3, pp. 37–44, May–June, 2015.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Korzhevskii, D.E., Kirik, O.V. Brain Microglia and Microglial Markers. Neurosci Behav Physi 46, 284–290 (2016). https://doi.org/10.1007/s11055-016-0231-z

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11055-016-0231-z

Keywords

Navigation