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Systemic Inflammation as a Driver of Brain Injury: the Astrocyte as an Emerging Player

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A Correction to this article was published on 26 May 2020

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Abstract

Severe systemic inflammation has strong effects on brain functions, promoting permanent neurocognitive dysfunction and high mortality rates. Additionally, hippocampal damage seems to be directly involved in this process and astrocytes play an important role in neuroinflammation and in the neuroimmune response. However, the contribution of the astrocytes to the pathology of acute brain dysfunction is not well understood. Recently, our group established a protocol for obtaining astrocyte cultures from mature brain to allow the characterization of these cells and their functions under pathologic conditions. The present study was designed to characterize astrocyte function after acute systemic inflammation induced by cecal ligation and perforation (CLP). Hippocampal astrocyte cultures from CLP animals presented increased levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-18, and cyclooxygenase-2 and decreased levels of IL-10. This proinflammatory profile was accompanied by an increase in Toll-like receptor (TLR)2 mRNA expression levels and no change either in TLR4 or in vascular endothelial growth factor (VEGF) gene expression. These alterations were associated with increased expressions of p21, nuclear factor kappa B (NFκB), and inducible nitric oxide synthase (iNOS) in astrocytes from CLP animals. The same parameters were also evaluated in whole hippocampal tissue, but differences in this profile were found compared to hippocampal astrocyte cultures from CLP, reflecting an interaction between other central nervous system cell types, which may mask specific astrocytic changes. These results improve our understanding of the mechanisms by which astrocytes react against systemic inflammation, and suggest these cells to be potential targets for therapeutic modulation.

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  • 26 May 2020

    The givenname ���Paola��� of the author Paola Haack Amaral Roppa (Roppa, P.H.A.) should be corrected to read Ricardo Haack Amaral Roppa (Roppa, R.H.A.) as presented above.

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Acknowledgements

This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Federal University of Rio Grande do Sul (UFRGS), and Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção (INCTEN/CNPq).

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Authors and Affiliations

  1. Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600—Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil

    Bruna Bellaver, João Paulo dos Santos, Larissa Daniele Bobermin, Paola Haack Amaral Roppa, Carlos-Alberto Gonçalves, Diogo Onofre Souza & André Quincozes-Santos

  2. Programa de Pós-Graduação em Medicina: Ciências Médicas, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Douglas Teixeira Leffa & Iraci Lucena da Silva Torres

  3. Unidade de Experimentação Animal, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Douglas Teixeira Leffa & Iraci Lucena da Silva Torres

Authors
  1. Bruna Bellaver
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  2. João Paulo dos Santos
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  3. Douglas Teixeira Leffa
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  4. Larissa Daniele Bobermin
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  5. Paola Haack Amaral Roppa
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  6. Iraci Lucena da Silva Torres
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  7. Carlos-Alberto Gonçalves
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  8. Diogo Onofre Souza
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  9. André Quincozes-Santos
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Corresponding authors

Correspondence to Bruna Bellaver or André Quincozes-Santos.

Ethics declarations

All animal experiments were performed in accordance with the National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals and the Brazilian Society for Neuroscience and Behavior’s recommendations for animal care. The experimental protocols were approved by the Federal University of Rio Grande do Sul Animal Care and Use Committee (process number 29180).

Conflict of Interest

The authors declare there are no conflicts of interest.

Electronic supplementary material

Supplementary Fig. 1

Inflammatory profile in the whole hippocampus. (A) TNF-α, (B) IL-1β and (G) COX-2 mRNA expression levels. (C) TNF-α, (D) IL-1β, (E) IL-6, (F) IL-18 and MCP-1 levels. Data represent the means + S.E.M. of groups (n= 6-8). *P <0.05, **P <0.01 and ***P <0.001 (t test), compared to the sham group. (TIFF 2874 kb)

High Resolution Image (GIF 54 kb)

Supplementary Fig. 2

CLP promoted increases in mRNA expression levels of (A) NFκB and (B) iNOS in hippocampal tissue. Data represent the means + S.E.M. of groups (n= 6). **P <0.01 (t test), compared to the sham group. (TIFF 1300 kb)

High Resolution Image (GIF 18 kb)

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Bellaver, B., dos Santos, J.P., Leffa, D.T. et al. Systemic Inflammation as a Driver of Brain Injury: the Astrocyte as an Emerging Player. Mol Neurobiol 55, 2685–2695 (2018). https://doi.org/10.1007/s12035-017-0526-2

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