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Aging and Microglial Response following Systemic Stimulation with Escherichia coli in Mice
Inge C M Hoogland1, Dunja Westhoff1, Joo-Yeon Engelen-Lee1
1Department of Neurology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Abstract:
Systemic infection is an important risk factor for the development cognitive impairment and neurodegeneration in older people. Animal experiments show that systemic challenges with live bacteria cause a neuro-inflammatory response, but the effect of age on this response in these models is unknown. Young (2 months) and middle-aged mice (13-14 months) were intraperitoneally challenged with live Escherichia coli (E. coli) or saline. The mice were sacrificed at 2, 3 and 7 days after inoculation; for all time points, the mice were treated with ceftriaxone (an antimicrobial drug) at 12 and 24 h after inoculation. Microglial response was monitored by immunohistochemical staining with an ionized calcium-binding adaptor molecule 1 (Iba-1) antibody and flow cytometry, and inflammatory response by mRNA expression of pro- and anti-inflammatory mediators. We observed an increased microglial cell number and moderate morphologically activated microglial cells in middle-aged mice, as compared to young mice, after intraperitoneal challenge with live E. coli. Flow cytometry of microglial cells showed higher CD45 and CD11b expressions in middle-aged infected mice compared to young infected mice. The brain expression levels of pro-inflammatory genes were higher in middle-aged than in young infected mice, while middle-aged infected mice had similar expression levels of these genes in the systemic compartment. We conclude that systemic challenge with live bacteria causes an age-dependent neuro-inflammatory and microglial response. Our data show signs of an age-dependent disconnection of the inflammatory transcriptional signature between the brain and the systemic compartment.
Insights
Systemic infection triggers age-dependent neuroinflammation. Middle-aged mice show heightened microglial activation and brain inflammatory responses compared to young mice following E. coli infection.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Systemic infections are linked to cognitive decline and neurodegeneration in the elderly.
- Previous studies indicate systemic bacterial challenges induce neuroinflammation in animal models.
- The impact of aging on this neuroinflammatory response remains largely unexplored.
Purpose of the Study:
- To investigate the age-dependent effects of systemic bacterial infection on neuroinflammation and microglial response.
- To compare the neuroinflammatory and microglial activation between young and middle-aged mice challenged with live Escherichia coli.
Main Methods:
- Young (2-month-old) and middle-aged (13-14-month-old) mice were intraperitoneally injected with live Escherichia coli (E. coli) or saline.
- Mice were treated with ceftriaxone at 12 and 24 hours post-inoculation and sacrificed at 2, 3, and 7 days.
- Microglial activation was assessed using Iba-1 immunohistochemistry and flow cytometry (CD45, CD11b expression).
- Inflammatory response was evaluated by measuring mRNA expression of pro- and anti-inflammatory mediators in brain and systemic compartments.
Main Results:
- Middle-aged mice exhibited increased microglial cell numbers and morphological activation compared to young mice after E. coli challenge.
- Flow cytometry revealed higher CD45 and CD11b expression on microglial cells in middle-aged infected mice.
- Pro-inflammatory gene expression in the brain was significantly higher in middle-aged infected mice than in young infected mice.
- Interestingly, gene expression levels of inflammatory mediators in the systemic compartment were similar between age groups.
Conclusions:
- Systemic challenge with live bacteria elicits an age-dependent neuroinflammatory and microglial response.
- Aging appears to disconnect the inflammatory transcriptional signature between the brain and the systemic compartment during infection.
