Protective effect of the long pentraxin PTX3 against histone-mediated endothelial cell cytotoxicity in sepsis

Kenji Daigo, Makoto Nakakido, Riuko Ohashi, Rie Fukuda, Koichi Matsubara, Takashi Minami, Naotaka Yamaguchi, Kenji Inoue, Shuying Jiang, Makoto Naito, Kouhei Tsumoto, Takao Hamakubo

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numberra88
JournalScience Signaling
Volume7
Issue number343
DOIs
Publication statusPublished - Sep 16 2014

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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