High-Mobility Group Box 1 Mediates Persistent Splenocyte Priming in Sepsis Survivors

Abstract

Severe sepsis is a life-threatening complication of infection and injury affecting more than 700,000 people in the United States each year. Two thirds of patients with severe sepsis will survive to be discharged. Survivors have high incidence of cognitive impairment, immune dysregulation, functional impairments with marked disability, and 5-year mortality rates of 82%. High-mobility group box 1 (HMGB1) is necessary and sufficient mediator of sepsis pathogenesis in experimental models of this syndrome. The spleen is a crucial organ in the immune response to severe infection, and splenocyte dysfunction occurs in sepsis survivors. We hypothesized that HMGB1 plays a key role in mediating the immune dysfunction of splenocytes in sepsis survivors. Mice that survived cecal ligation and puncture–induced sepsis develop persistent splenomegaly; furthermore, splenocytes derived from sepsis survivors had enhanced responses to lipopolysaccharide ex vivo. Administration of neutralizing anti-HMGB1 antibody to sepsis survivors attenuated development of splenomegaly and reversed splenocyte priming. Splenocytes exposed to HMGB1 and subsequently challenged with cognate ligands to Toll-like receptor 2 (TLR2,) TLR4, TLR9, and RAGE (receptor for advanced glycation end product) receptors had enhanced cytokine release as compared with splenocytes not previously exposed to HMGB1. Exposure of TLR2−/−, TLR9−/−, or RAGE−/− splenocytes to HMGB1 enhanced responses to other TLR receptor ligands; in contrast, HMGB1 failed to prime TLR4−/− splenocytes. These findings indicate that exposure to HMGB1 enhances splenocyte responses to secondary inflammatory challenges, a priming effect dependent on TLR4, and that anti-HMGB1 monoclonal antibody may be beneficial in sepsis survivors.

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

“…Other redox forms (frHMGB1 and oxHMGB1) exhibited negligible binding to MD-2 and were incapable of inducing TLR4 signaling. Of note, dsHMGB1 is sufficient to prime the microglial pro-inflammatory response to an immune challenge (see section 3.4. below), which is consistent with the priming qualities of HMGB1 in peripheral macrophages (Valdes-Ferrer et al, 2013). The last form of HMGB1 occurs under a state of complete oxidation wherein each cysteine is fully oxidized to a sulfonyl form and is not associated with any biological function (oxHMGB1).…”

Molecular mechanism and therapeutic modulation of high mobility group box 1 release and action: an updated review

“…At a late stage of infection, the PAMPs-mediated inflammatory response may be accompanied by unintended cell injury and DAMPs release that further amplifies the cytokine storm to precipitate organ dysfunction [164] ( Figure 1 and Figure 2 ). This possibility is supported by recent findings that HMGB1 is persistently elevated during a late stage of sepsis despite the cessation of initial infection [165], and contributes to the long-term pathological consequence of sepsis. Although the microbial infection-induced sepsis is similar to the sterile injury-elicited systemic inflammatory response syndrome (SIRS) [38,166], it may be more advantageous to develop strategies that specifically attenuate DAMPs-mediated inflammatory responses without compromising the PAMPs-mediated innate immunity.…”

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

“…These changes, combined with the reduction in the band pass filtering properties of the dendrites- which will become less tuned to inputs in the theta frequency range- and the change in the phase response, may alter cognitive processes [38, 65]. The HCN1 reduction could therefore contribute to the cognitive deficits induced by LPS in animals and provoked by sepsis in humans- which are chiefly mediated by IL-1β and HMGB1 [17, 66-68], and more in general in CNS disorders associated with neuroinflammation [38, 69, 70]. Of note, neuroinflammation and HCN1 downregulation are co-existing phenomena in epilepsy [20] and PD [3] and LPS also reduces I h currents in myocytes [71], suggesting that these channels are particularly sensitive to an inflammatory challenge.…”