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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00110

MICROGLIAL ACTIVATION AFTER SYSTEMIC STIMULATION WITH LIPOPOLYSACCHARIDE AND ESCHERICHIA COLI

 Inge C. Hoogland1, Dunja Westhoff1, Joo-Yeon Engelen-Lee1, Jeroen Melief2, Mercedes Valls Séron1,  Judith H. Houben-Weerts1,  Inge Huitinga2,  David J. Van Westerloo3, Tom van der Poll4, Willem A. van Gool1 and Diederik van de Beek1*
  • 1Neurology, Academic Medical Center (AMC), Netherlands
  • 2Netherlands Institute for Neuroscience (KNAW), Netherlands
  • 3Intensive Care Medicine, Leiden University Medical Center, Netherlands
  • 4Academic Medical Center (AMC), Netherlands

Background: Microglial activation after systemic infection has been suggested to mediate sepsis-associated delirium. A systematic review of animal studies suggested distinct differences between microglial activation after systemic challenge with live bacteria and lipopolysaccharide (LPS). Here, we describe a mouse model of microglial activation after systemic challenge with live Escherichia coli (E. coli) and compare results with systemic challenge with LPS.
Methods: 60 mice were intraperitoneally injected with E. coli (1x104 colony-forming units) and sacrificed at 12, 20, 48 and 72h after inoculation. For 48 and 72h time points, mice were treated with ceftriaxone. 30 mice were intraperitoneally injected with LPS (5 mg/kg) and sacrificed 3 and 48h after inoculation; 48 control mice were intraperitoneally injected with isotonic saline. Microglial response was monitored by immunohistochemical staining with Iba-1 antibody and flow cytometry; and inflammatory response by mRNA expression of pro- and anti-inflammatory mediators.
Results: Mice infected with live E. coli showed microglial activation 72h post inoculation, with increased cell number in cortex (p=0.0002), hippocampus (p=0.003), and thalamus (p=0.0001), but not in the caudate nucleus/putamen (p=0.33), as compared to controls. At 72h, flow cytometry of microglia from E. coli infected mice showed increased cell size (p=0.03) and CD45 expression (p=0.03), but no increase in CD11b expression, and no differences in brain mRNA expression of inflammatory mediators as compared to controls. In mice with systemic LPS stimulation, microglial cells were morphologically activated at the 48h time point with increased cell numbers in cortex (p=0.002 ), hippocampus (p=0.0003), thalamus (p=0.007) and caudate nucleus/putamen (p<0.0001), as compared to controls. At 48h, flow cytometry of microglia from LPS stimulated mice showed increased cell size (p=0.03), CD45 (p=0.03) and CD11b (p=0.04) expression. Brain mRNA expression of TNF-α (p=0.02), IL-1β (p=0.02) and MCP-1 (p=0.03) were increased as compared to controls.
Interpretation: Systemic challenge with live E. coli causes a neuro-inflammatory response, but this response occurs at a later time point and is less vigorous as compared to LPS stimulation. The E. coli model mimics the clinical situation of infection associated delirium more closely than stimulation with supra-natural LPS.

Keywords: Microglia, microglial activation, Systemic infection, Lipopolysaccaride, Escherichia coli, Neuro-inflammation, mouse model

Received: 17 Jan 2018; Accepted: 05 Apr 2018.

Edited by:

Nicola Maggio, Sheba Medical Center, Israel

Reviewed by:

Aniko Korosi, University of Amsterdam, Netherlands
Christiane CHARRIAUT-MARLANGUE, Institut National de la Santé et de la Recherche Médicale (INSERM), France  

Copyright: © 2018 Hoogland, Westhoff, Engelen-Lee, Melief, Valls Séron, Houben-Weerts, Huitinga, Van Westerloo, van der Poll, van Gool and van de Beek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Diederik van de Beek, Academic Medical Center (AMC), Neurology, Amsterdam, Netherlands, d.vandebeek@amc.uva.nl