Inorganic Polyphosphate Protects Against Lipopolysaccharide-Induced Lethality and Tissue Injury Through Regulation of Macrophage Recruitment

Biochem Pharmacol. 2019 Jan;159:96-105. doi: 10.1016/j.bcp.2018.11.017. Epub 2018 Nov 22.

Abstract

Sepsis is an etiologically complex and often fatal inflammatory process involving a multitude of cytokine signaling pathways. Tumor necrosis factor α (TNFα) acts as a central regulator of the acute-phase inflammatory response by recruiting immune cells, including circulating monocyte/macrophages, to sites of infection or tissue damage. Inorganic polyphosphate (polyP), a linear polymer of orthophosphate residues, has been found in almost all cells and tissues, but its functions in immunity remain largely unknown. In this study, we show that pre- or post-treatment of mice with polyP150 (average chain length of 150 phosphate residues) markedly increases survival from lipopolysaccharide (LPS)-induced shock and inhibits macrophage recruitment to the liver and lungs, resulting in protection against tissue injury. In accord with these in vivo results, pretreatment of cultured peritoneal macrophages with polyP150 inhibited chemotaxis and actin polarization in response to TNFα. PolyP150 also inhibited phosphorylation of stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38, two downstream signaling molecules of the TNFα cascade, thereby preventing cyclooxygenase-2 gene expression by macrophages. These findings suggest that polyP150 inhibits recruitment of macrophages into organs by regulating the TNFα-JNK/p38 pathway, which may, in turn, protect against multi-organ dysfunction and lethality induced by LPS. Our findings identify polyP regulation as a novel therapeutic target for sepsis.

Keywords: Inorganic polyphosphate; Lipopolysaccharide; Macrophage; Sepsis; Tumor necrosis factor α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemotaxis / drug effects
  • Cyclooxygenase 2 / genetics
  • Gene Expression Regulation / drug effects
  • Lipopolysaccharides / toxicity*
  • Liver / drug effects
  • Liver / pathology
  • Lung / drug effects
  • Lung / pathology
  • MAP Kinase Signaling System / drug effects
  • Macrophages, Peritoneal / drug effects*
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / pathology
  • Male
  • Mice, Inbred Strains
  • Nitric Oxide Synthase Type II / genetics
  • Phosphates / chemistry
  • Phosphates / pharmacology
  • Polyphosphates / chemistry
  • Polyphosphates / pharmacology*
  • Shock, Septic / chemically induced
  • Shock, Septic / drug therapy*
  • Shock, Septic / mortality
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Lipopolysaccharides
  • Phosphates
  • Polyphosphates
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • p38 Mitogen-Activated Protein Kinases