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Systemic inflammation and microglial activation: systematic review of animal experiments
Inge C M Hoogland1, Carin Houbolt2, David J van Westerloo3
1Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. i.c.hoogland@amc.uva.nl.
Background:
Animal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated delirium. We systematically reviewed animal experiments related to the effects of systemic inflammation on the microglial and inflammatory response in the brain.
Methods:
We searched PubMed between January 1, 1950 and December 1, 2013 and Embase between January 1, 1988 and December 1, 2013 for animal studies on the influence of peripheral inflammatory stimuli on microglia and the brain. Identified studies were systematically scored on methodological quality. Two investigators extracted independently data on animal species, gender, age, and genetic background; number of animals; infectious stimulus; microglial cells; and other inflammatory parameters in the brain, including methods, time points after inoculation, and brain regions.
Results:
Fifty-one studies were identified of which the majority was performed in mice (n = 30) or in rats (n = 19). Lipopolysaccharide (LPS) (dose ranging between 0.33 and 200 mg/kg) was used as a peripheral infectious stimulus in 39 studies (76 %), and live or heat-killed pathogens were used in 12 studies (24 %). Information about animal characteristics such as species, strain, sex, age, and weight were defined in 41 studies (80 %), and complete methods of the disease model were described in 35 studies (68 %). Studies were also heterogeneous with respect to methods used to assess microglial activation; markers used mostly were the ionized calcium binding adaptor molecule-1 (Iba-1), cluster of differentiation 68 (CD68), and CD11b. After LPS challenge microglial activation was seen 6 h after challenge and remained present for at least 3 days. Live Escherichia coli resulted in microglial activation after 2 days, and heat-killed bacteria after 2 weeks. Concomitant with microglial response, inflammatory parameters in the brain were reviewed in 23 of 51 studies (45 %). Microglial activation was associated with an increase in Toll-like receptor (TLR-2 and TLR-4), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) messenger ribonucleic acid (mRNA) expression or protein levels.
Interpretation:
Animal experiments robustly showed that peripheral inflammatory stimuli cause microglial activation. We observed distinct differences in microglial activation between systemic stimulation with (supranatural doses) LPS and live or heat-killed bacteria.
Insights
Peripheral inflammatory stimuli activate brain microglia, a key factor in sepsis-associated delirium. Different stimuli, like lipopolysaccharide (LPS) and bacteria, induce distinct microglial responses over time.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Peripheral inflammatory stimuli can activate brain microglial cells.
- Microglia play a crucial role in sepsis-associated delirium.
- Systemic inflammation influences the brain's microglial and inflammatory response.
Purpose of the Study:
- To systematically review animal experiments on the effects of peripheral inflammatory stimuli on brain microglia.
- To analyze the impact of systemic inflammation on microglial activation and brain inflammatory responses in animal models.
Main Methods:
- Systematic review of animal studies from PubMed and Embase (1950-2013).
- Data extraction on animal characteristics, infectious stimuli, microglial markers (Iba-1, CD68, CD11b), and inflammatory parameters.
- Assessment of methodological quality and heterogeneity of included studies.
Main Results:
- Fifty-one studies were reviewed, primarily using mice and rats.
- Lipopolysaccharide (LPS) was the most common stimulus (76%), followed by pathogens (24%).
- Microglial activation occurred within 6 hours after LPS and persisted for at least 3 days; bacterial stimuli showed longer activation times (2 days to 2 weeks).
- Microglial activation correlated with increased expression of Toll-like receptors (TLR-2, TLR-4), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β).
Conclusions:
- Animal studies confirm that peripheral inflammatory stimuli robustly induce microglial activation in the brain.
- Distinct differences in microglial activation patterns were observed between LPS and bacterial stimuli.