The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming
Open accessAbstract
UNLABELLED: Amplified neuroinflammatory responses following an immune challenge occur with normal aging and can elicit or exacerbate neuropathology. The mechanisms mediating this sensitized or "primed" immune response in the aged brain are not fully understood. The alarmin high mobility group box 1 (HMGB1) can be released under chronic pathological conditions and initiate inflammatory cascades. This led us to investigate whether HMGB1 regulates age-related priming of the neuroinflammatory response. Here, we show that HMGB1 protein and mRNA were elevated in the hippocampus of unmanipulated aged rats (24-month-old F344XBN rats). Furthermore, aged rats had increased HMGB1 in the CSF, suggesting increased HMGB1 release. We demonstrate that blocking HMGB1 signaling with an intracisterna magna (ICM) injection of the competitive antagonist to HMGB1, Box-A, downregulates basal expression of several inflammatory pathway genes in the hippocampus of aged rats. This indicates that blocking the actions of HMGB1 might reduce age-associated inflammatory priming. To test this hypothesis, we evaluated whether HMGB1 antagonism blocks the protracted neuroinflammatory and sickness response to peripheral Escherichia coli (E. coli) infection in aged rats. ICM pretreatment of aged rats with Box-A 24 h before E. coli infection prevented the extended hippocampal cytokine response and associated cognitive and affective behavioral changes. ICM pretreatment with Box-A also inhibited aging-induced potentiation of the microglial proinflammatory response to lipopolysaccharide ex vivo Together, these results suggest that HMGB1 mediates neuroinflammatory priming in the aged brain. Blocking the actions of HMGB1 appears to "desensitize" aged microglia to an immune challenge, thereby preventing exaggerated behavioral and neuroinflammatory responses following infection. SIGNIFICANCE STATEMENT: The world's population is aging, highlighting a need to develop treatments that promote quality of life in aged individuals. Normal aging is associated with precipitous drops in cognition, typically following events that induce peripheral inflammation (e.g., infection, surgery, heart attack). Peripheral immune stimuli cause exaggerated immune responses in the aged brain, which likely underlie these behavioral deficits. Here, we investigated whether the alarmin high mobility group box 1 (HMGB1) mediates age-associated "priming" of the neuroinflammatory response. HMGB1 is elevated in aged rodent brain and CSF. Blocking HMGB1 signaling downregulated expression of inflammatory pathway genes in aged rat brain. Further, HMGB1 antagonism prevented prolonged infection-induced neuroinflammatory and sickness responses in aged rats. Overall, blocking HMGB1 "desensitized" microglia in the aged brain, thereby preventing pathological infection-elicited neuroinflammatory responses.
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Elevated HMGB1 levels are found in the brain and cerebrospinal fluid of Alzheimer's disease patients and aged rodents and correlate with disease severity.
“elevated HMGB1 levels are found in the brain and CSF of AD patients and aged rodents and correlate with disease severity. 88 , 89 , 90”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [88]
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“62).”
- Authors
- Fonken, L. K., Frank, M. G., Kitt, M. M., D'Angelo, H. M., Norden, D. M., Weber, M. D., Barrientos, R. M., Godbout, J. P., Watkins, L. R., & Maier, S. F.
- Affiliations
- University of Colorado Boulder (US)
- The Ohio State University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-07-27
- Volume
- 36
- Issue
- 30
- Pages
- 7946-7956
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4961779
- OpenAlex
- W2490024771
- Cited by
- 139
- References
- 47
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 11 · 2023: 12 · 2022: 10 · 2021: 17 · 2020: 14 · 2019: 14 · 2018: 17 · 2017: 15 · 2016: 2
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG051902, R01AG028271, F32AG048672)
- National Institute of Dental and Craniofacial Research (R01DE021966)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- alarmins, neuroinflammation, brain aging, microglia, hippocampus, Escherichia coli infection, lipopolysaccharide, cytokine response, cognitive decline, emotional behavior, intracisternal injection
- MeSH terms
- Alarmins, Aging, Animals, Encephalitis, Hippocampus, Male, Tissue Distribution, Inflammation Mediators, HMGB1 Protein, Rats
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