Regional-specific activation of phagocytosis in the rat brain in the conditions of sepsis-associated encephalopathy
DOI:
https://doi.org/10.14739/2310-1210.2021.1.224921Keywords:
sepsis-associated encephalopathy, phagocytosis, microglia, CD68, transmission microscopy electionAbstract
In the condition of sepsis-associated encephalopathy (SAE), the brain neuroinflammatory response is considered as one of the most critical mechanisms of tissue damage and impaired cerebral homeostasis. The main cell population of the brain responsible for the immune surveillance is microglia, and its phagocytic activity is a fundamental function providing both homeostatic and damaging properties.
The aim of this study was to determine the immunohistochemical and ultrastructural specificity of the phagocytosis activation in different rat brain regions in the conditions of experimental sepsis.
Materials and methods. The study was conducted in Wistar rats: 5 sham-operated animals and 20 rats with cecum ligation and puncture (CLP). The immunohistochemical study of CD68 expression in the cortex, white matter, hippocampus, thalamus, caudate/putamen was carried out in the period of 20–48 h postoperatively. The cerebral cortex was examined using transmission electron microscopy.
Results. Beginning from the 20th h after CLP, there was a significant dynamic increase in the values of the relative area of CD68 expression, the number of immunopositive cells, as well as the percentage of immunopositive cells with amoeboid morphology in all animals of the CLP group, with a predominance of the indicators in the lethal group of rats. The highest levels of phagocytic activity were noted in the white matter and caudate/putamen in both the survived and non-survived animals. Ultrastructurally, the microgliocytes of the lethal group were characterized by signs of actively phagocytic cells and extensive glial-neuronal interaction; phagocytosing microglia in the survived animals showed an active involvement in the processes of necrotic debris elimination into the vasculature.
Conclusions. In the conditions of SAE, there is the early and dynamic increase in phagocytosis activation with the predominant localization in the brain white matter and caudate/putamen, which could conceivably indicate a special role of these brain areas in the mechanisms of neuroinflammatory response in the conditions of systemic inflammation. In the brain of non-survived animals, the phagocytosis indices are higher than in the group of survivors, which most likely indicates a natural response of microglia to more pronounced destructive processes, but it does not preclude a concurrent neurotoxic activity of CD68-positive cells on the surrounding tissue elements.
References
Shuliatnikova, T. V., & Shavrin, V. O. (2018). Sepsis associated encephalopathy and abdominal sepsis: current state of problem. Art of Medicine, (3), 158-165.
Lamar, C. D., Hurley, R. A., & Taber, K. H. (2011). Sepsis-Associated Encephalopathy: Review of the Neuropsychiatric Manifestations and Cognitive Outcome. The Journal of Neuropsychiatry and Clinical Neurosciences, 23(3), 237-241. https://doi.org/10.1176/jnp.23.3.jnp237
Lannes, N., Eppler, E., Etemad, S., Yotovski, P., & Filgueira, L. (2017). Microglia at center stage: a comprehensive review about the versatile and unique residential macrophages of the central nervous system. Oncotarget, 8(69), 114393-114413. https://doi.org/10.18632/oncotarget.23106
Li, Q., & Barres, B. A. (2018). Microglia and macrophages in brain homeostasis and disease. Nature Reviews Immunology, 18(4), 225-242. https://doi.org/10.1038/nri.2017.125
Michels, M., Sonai, B., & Dal-Pizzol, F. (2017). Polarization of microglia and its role in bacterial sepsis. Journal of Neuroimmunology, 303, 90-98. https://doi.org/10.1016/j.jneuroim.2016.12.015
Michels, M., Danielski, L. G., Dal-Pizzol, F., & Petronilho, F. (2014). Neuroinflammation: Microglial Activation During Sepsis. Current Neurovascular Research, 11(3), 262-270. https://doi.org/10.2174/1567202611666140520122744
Hoogland, I. C., Houbolt, C., van Westerloo, D. J., van Gool, W. A., & van de Beek, D. (2015). Systemic inflammation and microglial activation: systematic review of animal experiments. Journal of Neuroinflammation, 12, Article 114. https://doi.org/10.1186/s12974-015-0332-6
Shuliatnikova, T. V., & Shavrin, V. O. (2020). Ul'trastrukturnye osobennosti sostoyaniya astroglial'noi endosomal'noi sistemy pri sepsis-assotsiirovannoi entsefalopatii [Ultrastructural features of astroglial endosomal system state in sepsis-associated encephalopathy]. Pathologia, 17(1), 60-67. https://doi.org/10.14739/2310-1237.2020.1.203742 [in Russian].
De Biase, L. M., & Bonci, A. (2019). Region-Specific Phenotypes of Microglia: The Role of Local Regulatory Cues. The Neuroscientist, 25(4), 314-333. https://doi.org/10.1177/1073858418800996
Lee, J., Hamanaka, G., Lo, E. H., & Arai, K. (2019). Heterogeneity of microglia and their differential roles in white matter pathology. CNS Neuroscience & Therapeutics, 25(12), 1290-1298. https://doi.org/10.1111/cns.13266
Yeo, H. G., Hong, J. J., Lee, Y., Yi, K. S., Jeon, C. Y., Park, J., Won, J., Seo, J., Ahn, Y. J., Kim, K., Baek, S. H., Hwang, E. H., Kim, G., Jin, Y. B., Jeong, K. J., Koo, B. S., Kang, P., Lim, K. S., Kim, S. U., Huh, J. W., … Lee, S. R. (2019). Increased CD68/TGFβ Co-expressing Microglia/ Macrophages after Transient Middle Cerebral Artery Occlusion in Rhesus Monkeys. Experimental Neurobiology, 28(4), 458-473. https://doi.org/10.5607/en.2019.28.4.458
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W. S., Peterson, T. C., Wilton, D. K., Frouin, A., Napier, B. A., Panicker, N., Kumar, M., Buckwalter, M. S., Rowitch, D. H., Dawson, V. L., Dawson, T. M., Stevens, B., … Barres, B. A. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature, 541(7638), 481-487. https://doi.org/10.1038/nature21029
O'Neil, S. M., Witcher, K. G., McKim, D. B., & Godbout, J. P. (2018). Forced turnover of aged microglia induces an intermediate phenotype but does not rebalance CNS environmental cues driving priming to immune challenge. Acta Neuropathologica Communications, 6(1), Article 129. https://doi.org/10.1186/s40478-018-0636-8
Doyle, K. P., Cekanaviciute, E., Mamer, L. E., & Buckwalter, M. S. (2010). TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke. Journal of Neuroinflammation, 7, Article 62. https://doi.org/10.1186/1742-2094-7-62
Shulyatnikova, T., & Verkhratsky, A. (2020). Astroglia in Sepsis Associated Encephalopathy. Neurochemical Research, 45(1), 83-99. https://doi.org/10.1007/s11064-019-02743-2
Hoogland, I., Westhoff, D., Engelen-Lee, J. Y., Melief, J., Valls Serón, M., Houben-Weerts, J., Huitinga, I., van Westerloo, D. J., van der Poll, T., van Gool, W. A., & van de Beek, D. (2018). Microglial Activation After Systemic Stimulation With Lipopolysaccharide and Escherichia coli. Frontiers in Cellular Neuroscience, 12, Article 110. https://doi.org/10.3389/fncel.2018.00110
Li, Y., Zhang, R., Hou, X., Zhang, Y., Ding, F., Li, F., Yao, Y., & Wang, Y. (2017). Microglia activation triggers oligodendrocyte precursor cells apoptosis via HSP60. Molecular Medicine Reports, 16(1), 603-608. https://doi.org/10.3892/mmr.2017.6673
Michels, M., Abatti, M. R., Ávila, P., Vieira, A., Borges, H., Carvalho Junior, C., Wendhausen, D., Gasparotto, J., Tiefensee Ribeiro, C., Moreira, J., Gelain, D. P., & Dal-Pizzol, F. (2020). Characterization and modulation of microglial phenotypes in an animal model of severe sepsis. Journal of Cellular and Molecular Medicine, 24(1), 88-97. https://doi.org/10.1111/jcmm.14606
Michels, M., Ávila, P., Pescador, B., Vieira, A., Abatti, M., Cucker, L., Borges, H., Goulart, A. I., Junior, C. C., Barichello, T., Quevedo, J., & Dal-Pizzol, F. (2019). Microglial Cells Depletion Increases Inflammation and Modifies Microglial Phenotypes in an Animal Model of Severe Sepsis. Molecular Neurobiology, 56(11), 7296-7304. https://doi.org/10.1007/s12035-019-1606-2
Brown, G. C., & Neher, J. J. (2014). Microglial phagocytosis of live neurons. Nature Reviews Neuroscience, 15(4), 209-216. https://doi.org/10.1038/nrn3710
Fricker, M., Oliva-Martín, M. J., & Brown, G. C. (2012). Primary phagocytosis of viable neurons by microglia activated with LPS or Aβ is dependent on calreticulin/LRP phagocytic signalling. Journal of Neuroinflammation, 9, Article 196. https://doi.org/10.1186/1742-2094-9-196
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