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

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 the main 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 host-protective 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.

• Authors: Kenji Daigo, Makoto Nakakido, Riuko Ohashi, Rie Fukuda, Koichi Matsubara, Takashi Minami, Naotaka Yamaguchi, Kenji Inoue, Shuying Jiang, Makoto Naito, Kouhei Tsumoto, Takao Hamakubo
• Journal: Science signaling (Sci Signal) Vol. 7 Issue 343 Pg. ra88 (Sep 16 2014) ISSN: 1937-9145 [Electronic] United States
• PMID: 25227610 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014, American Association for the Advancement of Science.

Chemical References

• Histones
• Nerve Tissue Proteins
• neuronal pentraxin
• C-Reactive Protein

Topics

• Animals
• C-Reactive Protein (metabolism, pharmacology)
• Endothelial Cells (immunology)
• Enzyme-Linked Immunosorbent Assay
• Histones (metabolism)
• Immunity, Innate (immunology)
• Mice
• Nerve Tissue Proteins (metabolism, pharmacology)
• Protein Binding
• Protein Structure, Secondary (physiology)
• Protein Structure, Tertiary (physiology)
• Sepsis (immunology)
• Survival Analysis