Frontline Science: HMGB1 induces neutrophil dysfunction in experimental sepsis and in patients who survive septic shock

Abstract

Sepsis is accompanied by the initial activation of proinflammatory pathways and long-lasting immunosuppression that appears to contribute to late-occurring mortality. Although high-mobility group box 1 (HMGB1) is involved in many aspects of inflammation, its role in sepsis-induced immune suppression remains unclear. In this study, we examined HMGB1's contribution to neutrophil NADPH oxidase activity dysfunction and associated neutrophil-dependent bacterial clearance in mice subjected to sepsis and in patients who survive septic shock. Using a murine model of polymicrobial septic peritonitis, we demonstrated that treatment with anti-HMGB1 Ab significantly diminished sepsis-induced dysfunction of neutrophil NADPH oxidase activity. In a subsequent set of experiments, we found that blocking HMGB1 preserved the ability of neutrophils from patients recovering from septic shock to activate NADPH oxidase. Taken together, our data suggest that HMGB1 accumulation in the late phase of sepsis plays a specific role in the development of postsepsis immunosuppression and specifically affects neutrophil-dependent antibacterial defense mechanisms. Thus, blocking HMGB1 may be a promising therapeutic intervention to diminish the adverse effects of sepsis-induced immunosuppression.

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

“…Interestingly, HMGB1 expression was also markedly increased in our zebrafish sepsis model at the later stages of inflammation. HMGB1 accumulation in the late phase of sepsis in humans is known to play a major role in the development of postsepsis immunosuppression (52). Moreover, therapeutic blockade of HMGB1 in murine sepsis models has been shown to improve mortality (25).…”

Mitochondrial Dysfunction and Immune Cell Metabolism in Sepsis

“…However, recovery of metabolic activity and organ function is possible, and were strongly regulated by expression of markers of mitochondrial biogenesis such as PRARgamma-coactivator-1a (PGC-1a), nuclear respiratory factors 1 and 2 (NRF-1 and -2), and via repression of the biogenesis suppressor nuclear receptor interacting protein-140 (RIP140) [37464748]. Moreover, most recent pre-clinical studies, and our results, indicated that not only preservation, but also mitochondrial biogenesis is an essential step in reestablishing immune or tissue organ homeostasis during recovery from sepsis [495051]. …”

C5a anaphylatoxin and its role in critical illness‐induced organ dysfunction

“…In addition to TNF‐α production, C5a induces HMGB‐1 production through C5aR2 in mouse peritoneal macrophages . HMGB‐1 plays an important role in critical illness, driving further TNF‐α production by monocytes and reducing neutrophil respiratory burst activity . Paradoxically, macrophages seem to have enhanced functional responses following exposure to C5a, whereas neutrophil function is depressed.…”