Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia.
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.
Lamkanfi
Mohamed
M
Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA. Mohamed.Lamkanfi@VIB-UGent.be
Sarkar
Anasuya
A
Vande Walle
Lieselotte
L
Vitari
Alberto C
AC
Amer
Amal O
AO
Wewers
Mark D
MD
Tracey
Kevin J
KJ
Kanneganti
Thirumala-Devi
TD
Dixit
Vishva M
VM
D000818:Animals; D015153:Blotting, Western; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D012480:Salmonella Infections / Q000276:immunology / Q000378:metabolism
D024243:HMGB1 Protein; D020170:Caspase 1
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