Inorganic polyphosphate: a key modulator of inflammation

Inorganic polyphosphate (PolyP) is a molecule with prothrombotic and proinflammatory properties in blood. PolyP activates the NF-kappa B signaling pathway, increases the expression of cell surface adhesion molecules and disrupts the vascular barrier integrity of endothelial cells. PolyP-induced NF-kappa B activation and vascular hyperpermeability are regulated by the mammalian target of rapamycin complex-1 (mTORC1) and mTORC2 pathways, respectively. Through interaction with receptor for advanced glycation end products (RAGE) and P2Y1 receptors, PolyP dramatically amplifies the proinflammatory responses of nuclear proteins. Moreover, PolyPmediated activation of the contact pathway results in activation of the kallikrein-kinin system, which either directly or in cross-talk with the complement system induces inflammation in both cellular and animal systems. Thus, polyP is a novel therapeutic target for the treatment of metabolic and acute/chronic proinflammatory diseases, including severe sepsis, diabetes, cardiovascular disease and cancer. In this review, we discuss recent findings on the inflammatory properties of polyP and propose a model to explain the molecular mechanism of proinflammatory effects of this molecule in different systems.