TY - JOUR
T1 - Protective effect of the long pentraxin PTX3 against histone-mediated endothelial cell cytotoxicity in sepsis
AU - Daigo, Kenji
AU - Nakakido, Makoto
AU - Ohashi, Riuko
AU - Fukuda, Rie
AU - Matsubara, Koichi
AU - Minami, Takashi
AU - Yamaguchi, Naotaka
AU - Inoue, Kenji
AU - Jiang, Shuying
AU - Naito, Makoto
AU - Tsumoto, Kouhei
AU - Hamakubo, Takao
PY - 2014/9/16
Y1 - 2014/9/16
N2 - Pentraxin 3 (PTX3), a member of the long pentraxin subfamily within the family of pentraxins, is a soluble pattern recognition molecule that functions in the innate immune system. Innate immunity affords the infected host protection against sepsis, a potentially life-threatening inflammatory response to infection. Extracellular histones are considered to be themain cause of septic death because of their cytotoxic effect on endothelial cells, which makes them a potential therapeutic target. We found that PTX3 interacted with histones to form coaggregates, which depended on polyvalent interactions and disorder in the secondary structure of PTX3. PTX3 exerted a protective effect, both in vitro and in vivo, against histone-mediated cytotoxicity toward endothelial cells. Additionally, the intraperitoneal administration of PTX3 reduced mortality in mouse models of sepsis. The amino-terminal domain of PTX3, which was required for coaggregation with histones, was sufficient to protect against cytotoxicity. Our results suggest that the hostprotective effects of PTX3 in sepsis are a result of its coaggregation with histones rather than its ability to mediate pattern recognition. This long pentraxin-specific effect provides a potential basis for the treatment of sepsis directed at protecting cells from the toxic effects of extracellular histones.
AB - Pentraxin 3 (PTX3), a member of the long pentraxin subfamily within the family of pentraxins, is a soluble pattern recognition molecule that functions in the innate immune system. Innate immunity affords the infected host protection against sepsis, a potentially life-threatening inflammatory response to infection. Extracellular histones are considered to be themain cause of septic death because of their cytotoxic effect on endothelial cells, which makes them a potential therapeutic target. We found that PTX3 interacted with histones to form coaggregates, which depended on polyvalent interactions and disorder in the secondary structure of PTX3. PTX3 exerted a protective effect, both in vitro and in vivo, against histone-mediated cytotoxicity toward endothelial cells. Additionally, the intraperitoneal administration of PTX3 reduced mortality in mouse models of sepsis. The amino-terminal domain of PTX3, which was required for coaggregation with histones, was sufficient to protect against cytotoxicity. Our results suggest that the hostprotective effects of PTX3 in sepsis are a result of its coaggregation with histones rather than its ability to mediate pattern recognition. This long pentraxin-specific effect provides a potential basis for the treatment of sepsis directed at protecting cells from the toxic effects of extracellular histones.
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UR - http://www.scopus.com/inward/citedby.url?scp=84907532236&partnerID=8YFLogxK
U2 - 10.1126/scisignal.2005522
DO - 10.1126/scisignal.2005522
M3 - Article
C2 - 25227610
AN - SCOPUS:84907532236
VL - 7
JO - Science Signaling
JF - Science Signaling
SN - 1937-9145
IS - 343
M1 - ra88
ER -