The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming

Abstract

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.

High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory

“…Similarly, HMGB1, the endogenous danger signal that can stimulate inflammation through activation of pattern recognition receptors (Yanai, et al, 2012) was elevated by aging in the amygdala, but was not elevated with HFD. These results are consistent with previous findings that have shown aging-induced increases, and independently, HFD-induced increases in NLRP3 and HMGB1 gene expression (Fonken, et al, 2016, Robblee, et al, 2016, Sobesky, et al, 2016). We did not find potentiated expression of these two genes when aging and HFD were combined, consistent with previous findings that also failed to show amplified expression of NLRP3 or HMGB1 when HFD was combined with LPS (Sobesky, et al, 2016).…”

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

“…HMGB1, a ubiquitously expressed molecule, has been shown to increase in the circulation in rats with aging (Fonken et al ., 2016; Terrando et al ., 2016) and to increase RANKL expression in osteocytic cells (Yang et al ., 2008). However, we did not find changes in HMGB1 levels in the serum of old mice (Fig.…”

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases

“…HMGB1 has been well-established as a pro-inflammatory cytokine when it is released into the extracellular space and is produced by neurons, astrocytes, and microglia [48–50]. In addition, astrocytes and microglia can respond to HMGB1 by producing pro-inflammatory conditions, which is suggested to play an important role in neuroinflammation in neurodegenerative diseases [51–53].…”