Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming.

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.