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2016 ; 55
(ä): 215-224
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The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and
microglial priming: A role for the NLRP3 inflammasome
#MMPMID26482581
Frank MG
; Weber MD
; Fonken LK
; Hershman SA
; Watkins LR
; Maier SF
Brain Behav Immun
2016[Jul]; 55
(ä): 215-224
PMID26482581
show ga
The alarmin high mobility group box-1 (HMGB1) has been implicated as a key factor
mediating neuroinflammatory processes. Recent findings suggest that the redox
state of HMGB1 is a critical molecular feature of HMGB1 such that the reduced
form (fr-HMGB1) is chemotactic, while the disulfide form (ds-HMGB1) is
pro-inflammatory. The present study examined the neuroinflammatory effects of
these molecular forms as well as the ability of these forms to prime the
neuroinflammatory and microglial response to an immune challenge. To examine the
neuroinflammatory effects of these molecular forms in vivo, animals were
administered intra-cisterna magna (ICM) a single dose of fr-HMGB1 (10?g),
ds-HMGB1 (10?g) or vehicle and basal pro-inflammatory effects were measured 2 and
24h post-injection in hippocampus. Results of this initial experiment
demonstrated that ds-HMGB1 increased hippocampal pro-inflammatory mediators at 2h
(NF-?BI? mRNA, NLRP3 mRNA and IL-1? protein) and 24h (NF-?BI? mRNA, TNF? mRNA,
and NLRP3 protein) after injection. fr-HMGB1 had no effect on these mediators.
These neuroinflammatory effects of ds-HMGB1 suggested that ds-HMGB1 may function
to prime the neuroinflammatory response to a subsequent immune challenge. To
assess the neuroinflammatory priming effects of these molecular forms, animals
were administered ICM a single dose of fr-HMGB1 (10?g), ds-HMGB1 (10?g) or
vehicle and 24h after injection, animals were challenged with LPS (10?g/kg IP) or
vehicle. Neuroinflammatory mediators and the sickness response (3, 8 and 24h
after injection) were measured 2h after immune challenge. We found that ds-HMGB1
potentiated the neuroinflammatory (NF-?BI? mRNA, TNF? mRNA, IL-1? mRNA, IL-6
mRNA, NLRP3 mRNA and IL-1? protein) and sickness response (reduced social
exploration) to LPS challenge. fr-HMGB1 failed to potentiate the
neuroinflammatory response to LPS. To examine whether these molecular forms of
HMGB1 directly induce neuroinflammatory effects in isolated microglia, whole
brain microglia were isolated and treated with fr-HMGB1 (0, 1, 10, 100, or
1000ng/ml) or ds-HMGB1 (0, 1, 10, 100, or 1000ng/ml) for 4h and pro-inflammatory
mediators measured. To assess the effects of these molecular forms on microglia
priming, whole brain microglia were pre-exposed to these forms of HMGB1 (0, 1,
10, 100, or 1000ng/ml) and subsequently challenged with LPS (10ng/ml). We found
that ds-HMGB1 increased expression of NF-?BI? mRNA and NLRP3 mRNA in isolated
microglia, and potentiated the microglial pro-inflammatory response (TNF? mRNA,
IL-1? mRNA and IL-1? protein) to LPS. fr-HMGB1 failed to potentiate the
microglial pro-inflammatory response to LPS. Consistent with prior reports, the
present findings demonstrate that the disulfide form of HMGB1 not only
potentiates the neuroinflammatory response to a subsequent immune challenge in
vivo, but also potentiates the sickness response to that challenge. Moreover, the
present findings demonstrate for the first time that ds-HMGB1 directly
potentiates the microglia pro-inflammatory response to an immune challenge, a
finding that parallels the effects of ds-HMGB1 in vivo. In addition, ds-HMGB1
induced expression of NLRP3 and NF-?BI? in vivo and in vitro suggesting that the
NLRP3 inflammasome may play role in the priming effects of ds-HMGB1. Taken
together, the present results suggest that the redox state of HMGB1 is a critical
determinant of the priming properties of HMGB1 such that the disulfide form of
HMGB1 induces a primed immunophenotype in the CNS, which may result in an
exacerbated neuroinflammatory response upon exposure to a subsequent
pro-inflammatory stimulus.