Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia
M Lamkanfi, A Sarkar, L Vande Walle… - The Journal of …, 2010 - journals.aai.org
The Journal of immunology, 2010•journals.aai.org
Endotoxin administration recapitulates many of the host responses to sepsis. Inhibitors of the
cysteine protease caspase 1 have long been sought as a therapeutic because mice lacking
caspase 1 are resistant to LPS-induced endotoxic shock. According to current thinking,
caspase 1-mediated shock requires the proinflammatory caspase 1 substrates IL-1β and IL-
18. We show, however, that mice lacking both IL-1β and IL-18 are normally susceptible to
LPS-induced splenocyte apoptosis and endotoxic shock. This finding indicates the existence …
cysteine protease caspase 1 have long been sought as a therapeutic because mice lacking
caspase 1 are resistant to LPS-induced endotoxic shock. According to current thinking,
caspase 1-mediated shock requires the proinflammatory caspase 1 substrates IL-1β and IL-
18. We show, however, that mice lacking both IL-1β and IL-18 are normally susceptible to
LPS-induced splenocyte apoptosis and endotoxic shock. This finding indicates the existence …
Abstract
Endotoxin administration recapitulates many of the host responses to sepsis. Inhibitors of the cysteine protease caspase 1 have long been sought as a therapeutic because mice lacking caspase 1 are resistant to LPS-induced endotoxic shock. According to current thinking, caspase 1-mediated shock requires the proinflammatory caspase 1 substrates IL-1β and IL-18. We show, however, that mice lacking both IL-1β and IL-18 are normally susceptible to LPS-induced splenocyte apoptosis and endotoxic shock. This finding indicates the existence of another caspase 1-dependent mediator of endotoxemia. Reduced serum high mobility group box 1 (HMGB1) levels in caspase 1-deficient mice correlated with their resistance to LPS. A critical role for HMGB1 in endotoxemia was confirmed when mice deficient for IL-1β and IL-18 were protected from a lethal dose of LPS by pretreatment with HMGB1-neutralizing Abs. We found that HMGB1 secretion from LPS-primed macrophages required the inflammasome components apoptotic speck protein containing a caspase activation and recruitment domain (ASC), caspase 1 and Nalp3, whereas HMGB1 secretion from macrophages infected in vitro with Salmonella typhimurium was dependent on caspase 1 and Ipaf. Thus, HMGB1 secretion, which is critical for endotoxemia, occurs downstream of inflammasome assembly and caspase 1 activation.
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