Microglial Activation After Systemic Stimulation With Lipopolysaccharide and Escherichia coli

• Published in: Frontiers in cellular neuroscience Vol. 12; p. 110
• Main Authors: Hoogland, Inge C M, Westhoff, Dunja, Engelen-Lee, Joo-Yeon, Melief, Jeroen, Valls Serón, Mercedes, Houben-Weerts, Judith H M P, Huitinga, Inge, van Westerloo, David J, van der Poll, Tom, van Gool, Willem A, van de Beek, Diederik
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 24.04.2018; Frontiers Media S.A
• Subjects: Bacteria; Bacterial infections; Caudate nucleus; CD11b antigen; CD45 antigen; Ceftriaxone; Cell number; Cell size; Delirium; Dementia; Disseminated infection; Drug dosages; E coli; Escherichia coli; Experiments; Flow cytometry; Gene expression; Hippocampus; IL-1β; Infections; Inflammation; Inoculation; Institutionalization; lipopolysaccharide; Lipopolysaccharides; Medicin och hälsovetenskap; Microglia; microglial activation; Microglial cells; Monocyte chemoattractant protein 1; neuro-inflammation; Neurodegeneration; Neuroscience; Older people; Putamen; Sepsis; Systematic review; systemic infection; Thalamus; Tumor necrosis factor-α; Netherlands; neuro-inflammation; systemic infection; mouse model; Escherichia coli; lipopolysaccharide; microglia; microglial activation
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2018.00110

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 ( ) and compare results with systemic challenge with LPS. Sixty mice were intraperitoneally injected with (1 × 10 colony-forming units) and sacrificed at 12, 20, 48, and 72 h after inoculation. For 48 and 72 h time points, mice were treated with ceftriaxone. Thirty mice were intraperitoneally injected with LPS (5 mg/kg) and sacrificed 3 and 48 h 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. Mice infected with live showed microglial activation 72 h post-inoculation, with increased cell number in cortex ( = 0.0002), hippocampus ( = 0.003), and thalamus ( = 0.0001), but not in the caudate nucleus/putamen ( = 0.33), as compared to controls. At 72 h, flow cytometry of microglia from infected mice showed increased cell size ( = 0.03) and CD45 expression ( = 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 48 h time point with increased cell numbers in cortex ( = 0.002), hippocampus ( = 0.0003), thalamus ( = 0.007), and caudate nucleus/putamen ( < 0.0001), as compared to controls. At 48 h, flow cytometry of microglia from LPS stimulated mice showed increased cell size ( = 0.03), CD45 ( = 0.03), and CD11b ( = 0.04) expression. Brain mRNA expression of TNF-α ( = 0.02), IL-1β ( = 0.02), and MCP-1 ( = 0.03) were increased as compared to controls. Systemic challenge with live causes a neuro-inflammatory response, but this response occurs at a later time point and is less vigorous as compared to LPS stimulation.The model mimics the clinical situation of infection associated delirium more closely than stimulation with supra-natural LPS.