EBioMedicine (Jul 2016)

Histidine-Rich Glycoprotein Prevents Septic Lethality through Regulation of Immunothrombosis and Inflammation

  • Hidenori Wake,
  • Shuji Mori,
  • Keyue Liu,
  • Yuta Morioka,
  • Kiyoshi Teshigawara,
  • Masakiyo Sakaguchi,
  • Kosuke Kuroda,
  • Yuan Gao,
  • Hideo Takahashi,
  • Aiji Ohtsuka,
  • Tadashi Yoshino,
  • Hiroshi Morimatsu,
  • Masahiro Nishibori

DOI
https://doi.org/10.1016/j.ebiom.2016.06.003
Journal volume & issue
Vol. 9, no. C
pp. 180 – 194

Abstract

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Sepsis is a major cause of death worldwide. We show that a plasma protein histidine-rich glycoprotein (HRG) was decreased significantly in septic mice with cecal ligation and puncture (CLP) and supplementary treatment of septic mice with exogenous HRG improved survival, with strong inhibition of tight attachment of neutrophils to pulmonary vasculatures, subsequent immunothrombosis, DIC state, lung inflammation, hypercytokinemia, and activation of vascular endothelial cells (VECs). In contrast, knockdown of HRG by siRNA exacerbated lethality. Purified human HRG reversibly induced morphological changes in human neutrophils in vitro; induction of spherical shape with reduced microvilli and adhesiveness to VECs. HRG maintained the passage of neutrophils through microcapillaries and abolished production of reactive oxygen species. These results suggested that the supplementary therapy with HRG may provide a novel strategy for the treatment of sepsis through suppression of excessive systemic inflammation and immunothrombosis by keeping circulating neutrophils quiescent and preventing uncontrolled activation of VECs.

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