Immunomodulation of neutrophil granulocyte functions by bacterial polyphosphates

Abstract

Polyphosphates are highly conserved, linear polymers of monophosphates that reside in all living cells. Bacteria produce long chains containing hundreds to thousands of phosphate units, which can interfere with host defense to infection. Here, we report that intratracheal long‐chain polyphosphate administration to C57BL/6J mice resulted in the release of proinflammatory cytokines and influx of Ly6G+ polymorphonuclear neutrophils in the bronchoalveolar lavage fluid causing a disruption of the physiologic endothelial–epithelial small airway barrier and histologic signs of lung injury. Polyphosphate‐induced effects were attenuated after neutrophil depletion in mice. In isolated murine neutrophils, long‐chain polyphosphates modulated cytokine release induced by lipopolysaccharides (LPS) from Gram‐negative bacteria or lipoteichoic acid from Gram‐positive bacteria. In addition, long‐chain polyphosphates induced immune evasive effects in human neutrophils. In detail, long‐chain polyphosphates downregulated CD11b and curtailed the phagocytosis of Escherichia coli particles by neutrophils. Polyphosphates modulated the migration capacity by inducing CD62L shedding resulting in CD62Llow and CD11blow neutrophils. The release of IL‐8 induced by LPS was also significantly reduced. Pharmacologic blockade of PI3K with wortmannin antagonized long‐chain polyphosphate‐induced effects on LPS‐induced IL‐8 release. In conclusion, polyphosphates govern immunomodulation in murine and human neutrophils, suggesting polyphosphates as a therapeutic target for bacterial infections to restore innate immune defense.

Polyphosphate as an antithrombotic target and hemostatic agent

“…140,141 Lc-PolyP has recently been reported to govern immunomodulation in murine and human neutrophils via the PI3K/Akt signaling pathway. 142 (4) PolyP initiates the contact pathway leading to the release of bradykinin, a potent vasoactive peptide that promotes vasodilation and the infiltration of inflammatory factors and phagocytic cells stimulating the adaptive immune response. 143 Notably, the efficiency of lc-PolyP in activating the contact system is orders of magnitude higher than that of sc-PolyP.…”

“…In isolated murine neutrophils, lc-PolyP modulates cytokine release triggered by lipopolysaccharides (LPS) from Gram-negative bacteria or lipoteichoic acid from Gram-positive bacteria. 142 Sc-PolyP mediates neutrophil-endothelial cell interactions, promotes neutrophil migration, enhances recruitment and accumulation during bacterial infection, and can induce NETs. 166,211–213…”