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.

DNA and factor VII–activating protease protect against the cytotoxicity of histones

“…Not surprisingly, many plasma proteins that neutralize histones are highly negatively charged, such as heparin, 44 pentraxin-3, 45 C-reactive protein, 46 and inter-a inhibitor protein. 21 DNA may also efficiently neutralize the histone charge, and indeed, analogous to nucleosomes, we showed that both ssDNA and dsDNA neutralized the cytotoxicity induced by histones.…”

Pentraxin-3 Attenuates Renal Damage in Diabetic Nephropathy by Promoting M2 Macrophage Differentiation

“…Recently, several clinical investigations have demonstrated that elevated plasma Ptx3 levels are associated with cardiovascular [8,9] and chronic kidney diseases (CKD) [10,11]. Kenji Daigo et al demonstrated that the intraperitoneal administration of Ptx3 reduced mortality in mouse models of sepsis [12]. Furthermore, plasma Ptx3 levels are inversely associated with body mass index (BMI) suggesting that Ptx3 may play a role in obesity and metabolic syndrome [13,14].…”

The Protective Effect against Extracellular Histones Afforded by Long-Pentraxin PTX3 as a Regulator of NETs

“…These motifs confer on PTX3 N-terminal domain a propensity for forming a coiled-coil structure. The signal of the α-helix was detected by circular dichroic (CD) spectroscopy (8). Inforzato et al attributed the multimer formation of PTX3 to the inter- and intra-molecular disulfide bonds in the organization of the matrix (25) and proposed an asymmetric octamer structure for PTX3 based on biophysical analysis (26).…”

“…In the effort to understand the molecular mechanisms of PTX3–histone complex formation, both direct and high-affinity binding between PTX3 and histones has been reported. Of note, it was found that the binding induced coaggregation of PTX3 with histones due to a disorder of the PTX3 secondary structure (Figures 2A,B) (8). A cell-based assay revealed that PTX3 blocks histone-mediated cytotoxic activity toward endothelial cells.…”

“…They have bactericidal activity, but have also been shown to exert a cytotoxic effect on endothelial cells in sepsis. PTX3 has an ability to attenuate extracellular histone-mediated cytotoxicity through coaggregation (8). This implies that the role of PTX3 in NETs is not only to combat bacteria but also to mitigate the detrimental effects of NETs.…”