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The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming
#MMPMID27466339
Fonken LK
; Frank MG
; Kitt MM
; D'Angelo HM
; Norden DM
; Weber MD
; Barrientos RM
; Godbout JP
; Watkins LR
; Maier SF
J Neurosci
2016[Jul]; 36
(30
): 7946-56
PMID27466339
show ga
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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