High mobility group box-1 (
HMGB1) is an endogenous danger signal or
alarmin that mediates activation of the innate immune response including chemotaxis and pro-inflammatory
cytokine release.
HMGB1 has been implicated in the pathophysiology of several neuroinflammatory conditions including
ischemia,
traumatic brain injury, seizure and chronic
ethanol use. In the present review, the unique structural and functional properties of
HMGB1 will be explored including its affinity for multiple
pattern recognition receptors (TLR2/TLR4), redox sensitivity and adjuvant-like properties. In light of recent evidence suggesting that
HMGB1 may also mediate stress-induced sensitization of neuroinflammatory responses, mechanisms of
HMGB1 action in neuroinflammatory priming are explored. A model of neuroinflammatory priming is developed wherein
glucocorticoids induce synthesis and release of
HMGB1 from microglia, which signals through TLR2/TLR4, thereby priming the NLRP3
inflammasome. We propose that if GCs reach a critical threshold as during a fight/flight response, they may thus function as an
alarmin by inducing
HMGB1, thereby preparing an organism's innate immune system (NLRP3
inflammasome priming) for subsequent immune challenges such as injury,
trauma or
infection, which are more likely to occur during a fight/flight response. In doing so, GCs may confer a significant survival advantage by enhancing the central innate immune and sickness response to immune challenges.