Inorganic polyphosphate (polyP) elicits proinflammatory signaling responses in endothelial cells through interaction with two receptors, RAGE and P2Y1. We demonstrate here that polyP elicits proinflammatory signaling responses through activation of mTOR complexes 1 (mTORC1) and 2 (mTORC2) in endothelial cells. Thus, polyP effectively induced the phosphorylation of the mTORC1 substrate, p70S6K, in endothelial cells by an AKT-dependent but ERK-independent mechanism. Furthermore, it was found that activation of the PI3K/PLC/PKC/Ca2+ signaling axis is required for the polyP-mediated phosphorylation of p70S6K. The inhibition of mTORC1 by either rapamycin or by the siRNA knockdown of raptor (mTORC1-specific component) but not rictor (mTORC2-specific component) abrogated polyP-mediated phosphorylation of p70S6K. By contrast, the siRNA knockdown of rictor but not raptor eliminated the barrier disruptive effect of polyP, suggesting that the barrier permeability regulating function of polyP is mediated through activation of mTORC2. Specific NF-kB inhibitors abrogated polyP-mediated phosphorylation of p70S6K and rapamycin suppressed polyP-induced activation of NF-kB, suggesting both proinflammatory and mTOR signaling functions of polyP are linked. Finally, inhibitors of mTOR or its upstream signaling network eliminated polyP-mediated vascular leakage and leukocyte recruitment in animal models, suggesting that findings in cellular models are physiologically relevant.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.