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Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1β and anti-inflammatory IL-10 cytokines
Open accessAbstract
In the elderly, systemic infection is associated with an increased frequency of behavioral and cognitive complications. We have reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response and prolonged sickness/depressive-like behaviors in aged BALB/c mice. Therefore, the purpose of this study was to determine the degree to which LPS-induced neuroinflammation was associated with microglia-specific induction of neuroinflammatory mediators. Here, we show that peripheral LPS challenge caused a hyperactive microglial response in the aged brain associated with higher induction of inflammatory IL-1beta and anti-inflammatory IL-10. LPS injection caused a marked induction of mRNA expression of both IL-1beta and IL-10 in the cortex of aged mice compared to adults. In the next set of studies, microglia (CD11b(+)/CD45(low)) were isolated from the brain of adult and aged mice following experimental treatments. An age-dependent increase in major histocompatibility complex (MHC) class II mRNA and protein expression was detected in microglia. Moreover, peripheral LPS injection caused a more pronounced increase in IL-1beta, IL-10, Toll-like receptor (TLR)-2, and indoleamine 2,3-dioxygenase (IDO) mRNA levels in microglia isolated from aged mice than adults. Intracellular cytokine protein detection confirmed that peripheral LPS caused the highest increase in IL-1beta and IL-10 levels in microglia of aged mice. Finally, the most prominent induction of IL-1beta was detected in MHC II(+) microglia from aged mice. Taken together, these findings provide novel evidence that age-associated priming of microglia plays a central role in exaggerated neuroinflammation induced by activation of the peripheral innate immune system.
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“Indeed, increased intestinal inflammation driven by either LPS or bacterial infection correlates with elevated levels of microglial activation and release of pro-inflammatory cytokines (Riazi et al., 2008; Henry et al., 2009).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Henry et al., 2009
In the citing paper
“In both humans [62] and mice [52,63,64], aged microglia adopt a pro-inflammatory profile including higher expression of genes including TNFα, IL-6, and IL-1β, as well as markers of ‘priming’ such as CD11b and MHC-II (Figure 1).”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [63]
In the citing paper
“Subsequent studies showed that the excessive IL-1β protein produced in the aged brain after LPS challenge was derived from the primed (MHCII positive) microglia (Henry et al, 2009).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Henry et al, 2009
In the citing paper
“Although IL-10 expression may indicate a compensatory step against the pro-inflammatory response, IL-1β production in aged mice was not attenuated despite presence of IL-10 (Henry et al, 2009).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Henry et al, 2009
In the citing paper
“It is important to note that LPS enhances expression of pro-inflammatory (eg, IL-1β) and anti-inflammatory (eg, IL-10) mediators in aged mice compared with the adult (Henry et al, 2009).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Henry et al, 2009
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Metadata
- Authors
- Henry, C. J., Huang, Y., Wynne, A. M., & Godbout, J. P.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Godbout, Jonathan P.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 23
- Issue
- 3
- Pages
- 309-317
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC2692986
- OpenAlex
- W2159822434
- Cited by
- 565
- References
- 63
- Citations by year
- 2026: 22 · 2025: 23 · 2024: 26 · 2023: 26 · 2022: 35 · 2021: 39 · 2020: 38 · 2019: 29 · 2018: 42 · 2017: 36 · 2016: 47 · 2015: 41 · 2014: 40 · 2013: 38 · 2012: 33
- FWCI
- 11.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG033028)
- National Institute of Mental Health (R21MH077817)
- National Institute of Allergy and Infectious Diseases (R32-AI-05-5411)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- lipopolysaccharide challenge, neuroinflammation, aging, IL-1β, IL-10, MHC class II, TLR2, indoleamine 2,3-dioxygenase, microglia, cognitive aging, depression-like behavior, systemic infection
- MeSH terms
- Aging, Analysis of Variance, Animals, Brain, Cerebral Cortex, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Injections, Intraperitoneal, Lipopolysaccharides, Male, Mice, Inbred BALB C, RNA, Messenger, Polymerase Chain Reaction, Interleukin-10, Microglia, Mice, Interleukin-1beta
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