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

Abstract

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.

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

“…Recently, it has been reported that psychological and/or acute intense stressor exposure in the absence of overt tissue damage can evoke a detectable local and systemic sterile inflammatory response and that DAMPs may have a (Fleshner, 2013;Frank et al, 2015b;Maslanik et al, 2013;Miller et al, 2015).…”

“…A number of studies have demonstrated that prior exposure to acute or chronic stressors potentiates the neuroinflammatory and microglial proinflammatory response to a subsequent immune challenge (Frank et al, 2015b). Interestingly, we found that intracisterna magna administration of an HMGB1 antagonist (box A) before stress exposure blocked the potentiated ............................................................................................................................................................. microglial proinflammatory response to an immune challenge ex vivo.…”

“…The DAMP HMGB1 has been implicated in stress-induced priming of NLRP3 and the neuroinflammatory response to a subsequent immune challenge (Frank et al, 2015b). HMGB1 has a pivotal role in the induction of neuroinflammatory processes in neurodegenerative conditions (Fang et al, 2012), cerebral ischemia (Yang et al, 2010), traumatic brain injury (Corps et al, 2015), seizure (Vezzani, 2014), and ethanolinduced neurotoxicity (Zou and Crews, 2014).…”

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

“…Other studies find both acute and chronic alcohol increase neuroimmune signaling in the brain (Vetreno and Crews, 2012; Walter and Crews, 2017). Acute stress also increases brain expression of cytokines such as TNF‐ α , IL‐1 β , and Ccl2 (Knapp et al., 2016) and the danger signaling molecule, high mobility group box‐1 protein (HMGB1) (Frank et al., 2015; Weber et al., 2015). Stress sensitizes neuroimmune responses (Frank et al., 2015), and stress hormones that are generally anti‐inflammatory have been hypothesized to have the opposite effect of enhancing brain innate immune signaling under some circumstances (Frank et al., 2015; Sorrells et al., 2009).…”

“…Acute stress also increases brain expression of cytokines such as TNF‐ α , IL‐1 β , and Ccl2 (Knapp et al., 2016) and the danger signaling molecule, high mobility group box‐1 protein (HMGB1) (Frank et al., 2015; Weber et al., 2015). Stress sensitizes neuroimmune responses (Frank et al., 2015), and stress hormones that are generally anti‐inflammatory have been hypothesized to have the opposite effect of enhancing brain innate immune signaling under some circumstances (Frank et al., 2015; Sorrells et al., 2009). Further, studies in rats find partial restraint stress increases blood endotoxin and stress hormones, such as ACTH and corticosterone (CORT), as well as brain proinflammatory cytokines.…”