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Microglial Cells Depletion Increases Inflammation and Modifies Microglial Phenotypes in an Animal Model of Severe Sepsis

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Abstract

Sepsis-associated encephalopathy is highly prevalent and has impact both in early and late morbidity and mortality. The mechanisms by which sepsis induces brain dysfunction include neuroinflammation, disrupted blood–brain barrier, oxidative stress, and microglial activation, but the cellular and molecular mechanisms involved in these events are not completely understood. Our objective was to determine the effects of microglial depletion in the early systemic and brain inflammatory response and its impact in phenotypes expression in an animal model of sepsis. Animals were subjected to CLP, and depletion of microglial cells was accomplished by administration of (Lipo)-encapsulated clodronate and microglial repopulation by doxycycline. Clod-lip treatment was effective in decreasing microglia density in the hippocampus of animals. Pro-inflammatory cytokines were increased in the CLP+PBS, and liposomes administration increased even further these cytokines mainly 7 days, suggesting that microglial depletion exacerbates both local and systemic inflammation. In contrast, repopulation with doxycycline was able to revert the cytokine levels in both serum and cerebral structures on day 7 and 14 after repopulation. There were no differences in the correlation between M1 and M2 markers by real-time PCR, but immunohistochemistry showed significant increase in CD11b expression in CLP+PBS with greater expression in CLP + liposomes in the hippocampus. These results suggest that the depletion of microglia during severe sepsis development could be associated with early exacerbation of brain and systemic inflammation and repopulation is able to revert this condition, once a rapid neurological recovery is noticed until 7 days after sepsis.

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Acknowledgments

The authors acknowledge CAPES - 001, CNPQ, FAPESC, and UNESC.

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Authors and Affiliations

  1. Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil

    Monique Michels, Pricila Ávila, Bruna Pescador, Andriele Vieira, Mariane Abatti, Luana Cucker, Heloisa Borges, Amanda Indalécio Goulart, Celso Carvalho Junior & Felipe Dal-Pizzol

  2. Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    Tatiana Barichello & João Quevedo

  3. Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Tatiana Barichello & João Quevedo

  4. Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    João Quevedo

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  1. Monique Michels
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  2. Pricila Ávila
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Correspondence to Felipe Dal-Pizzol.

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Michels, M., Ávila, P., Pescador, B. et al. Microglial Cells Depletion Increases Inflammation and Modifies Microglial Phenotypes in an Animal Model of Severe Sepsis. Mol Neurobiol 56, 7296–7304 (2019). https://doi.org/10.1007/s12035-019-1606-2

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