4.7 Article

The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming

Journal

JOURNAL OF NEUROSCIENCE
Volume 36, Issue 30, Pages 7946-7956

Publisher

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1161-16.2016

Keywords

danger-associated molecular patterns; healthy aging; microglia; neuroimmunology; sickness behavior

Categories

Funding

  1. National Institutes of Health (NIH) [R01AG028271]
  2. NIH [F32AG048672]
  3. National Alliance for Research on Schizophrenia and Depression Young Investigator Grant - New York Women's Committee

Ask authors/readers for more resources

Amplified neuroinflammatory responses following an immune challenge occur with normal aging and can elicit or exacerbate neuropathology. The mechanisms mediating this sensitized or primed immuneresponse 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available