Inorganic polyphosphate protects against lipopolysaccharide-induced lethality and tissue injury through regulation of macrophage recruitment

Terashima-Hasegawa, Mikako; Ashino, Takashi; Kawazoe, Yumi; Shiba, Toshikazu; Manabe, Atsufumi; Numazawa, Satoshi

doi:10.1016/j.bcp.2018.11.017

Cited by 17 publications

(17 citation statements)

References 27 publications

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“…In addition to our oberservation that long-chain polyphosphates decrease local macrophage recruitment, it was recently reported that short-chain (P i~1 50) polyphosphates block the migration of macrophages and their intracellular actin polarization together with effects on cyclooxygenase-2, TNFα and the JNK/p38 pathway 23 . In contrast to our findings of longchain polyphosphates mediating detrimental effects in live E. coli sepsis, the short-chain (P i~1 50) polyphosphates protected from LPS-induced shock lethality 23 . This discrepancy supports the view that polyphosphate effects are variable for chain length, dose and the model of infection.…”

Section: Discussionmentioning

confidence: 49%

“…The differentiation of human macrophages from peripheral blood also appears regulated by platelet-derived, short-chain polyphosphates 24 . In addition to our oberservation that long-chain polyphosphates decrease local macrophage recruitment, it was recently reported that short-chain ( P i ~ 150) polyphosphates block the migration of macrophages and their intracellular actin polarization together with effects on cyclooxygenase-2, TNFα and the JNK/p38 pathway 23 . In contrast to our findings of long-chain polyphosphates mediating detrimental effects in live E. coli sepsis, the short-chain ( P i ~ 150) polyphosphates protected from LPS-induced shock lethality 23 .…”

Section: Discussionmentioning

confidence: 51%

“…To underscore the functional distinctions inherent in polyphosphate polymer sizes, mammalian-type, short-chain polyphosphates were less active or showed divergent properties for some readouts of inflammation 23 . Intriguingly, high concentrations and direct secretion of relatively long-chain polyphosphates in mammalian species is merely reported for the immune privileged brain through astrocytes 20,46 .…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports have suggested that short-sized, mammalian-derived polyphosphates regulate the functions of endothelial cells and astrocytes by signaling through the purinergic P2Y1 receptor and RAGE receptor 20,21 . Short-chain polyphosphates can modulate the migration, differentiation and functions of neutrophils and macrophages [22][23][24] .…”

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confidence: 99%

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Bacterial polyphosphates interfere with the innate host defense to infection

et al. 2020

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Polyphosphates are linear polymers and ubiquitous metabolites. Bacterial polyphosphates are long chains of hundreds of phosphate units. Here, we report that mouse survival of peritoneal Escherichia coli sepsis is compromised by long-chain polyphosphates, and improves with bacterial polyphosphatekinase deficiency or neutralization using recombinant exopolyphosphatase. Polyphosphate activities are chain-length dependent, impair pathogen clearance, antagonize phagocyte recruitment, diminish phagocytosis and decrease production of iNOS and cytokines. Macrophages bind and internalize polyphosphates, in which their effects are independent of P2Y1 and RAGE receptors. The M1 polarization driven by E. coli derived LPS is misdirected by polyphosphates in favor of an M2 resembling phenotype. Long-chain polyphosphates modulate the expression of more than 1800 LPS/TLR4-regulated genes in macrophages. This interference includes suppression of hundreds of type I interferonregulated genes due to lower interferon production and responsiveness, blunted STAT1 phosphorylation and reduced MHCII expression. In conclusion, prokaryotic polyphosphates disturb multiple macrophage functions for evading host immunity.

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Bacterial polyphosphates interfere with the innate host defense to infection

et al. 2020

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“…Depending on the length, dose and formulation, systemic delivery of polyP may entail risk of thrombosis. However, polyP has been administered safely in vivo , providing protection against endotoxin-induced sepsis in a mouse model (81). If validated, one could envisage using polyP for a wide range of disorders with excess complement activation.…”

Section: Relevance Of Polyp In Complementmentioning

confidence: 99%

Polyphosphates and Complement Activation

Conway

2019

Front. Med.

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To sustain life in environments that are fraught with risks of life-threatening injury, organisms have developed innate protective strategies such that the response to wounds is rapid and localized, with the simultaneous recruitment of molecular, biochemical, and cellular pathways that limit bleeding and eliminate pathogens and damaged host cells, while promoting effective healing. These pathways are both coordinated and tightly regulated, as their over- or under-activation may lead to inadequate healing, disease, and/or demise of the host. Recent advances in our understanding of coagulation and complement, a key component of innate immunity, have revealed an intriguing linkage of the two systems. Cell-secreted polyphosphate promotes coagulation, while dampening complement activation, discoveries that are providing insights into disease mechanisms and suggesting novel therapeutic strategies.

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Immunomodulation of neutrophil granulocyte functions by bacterial polyphosphates

et al. 2023

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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.

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Inorganic polyphosphate protects against lipopolysaccharide-induced lethality and tissue injury through regulation of macrophage recruitment

Cited by 17 publications

References 27 publications

Bacterial polyphosphates interfere with the innate host defense to infection

Bacterial polyphosphates interfere with the innate host defense to infection

Polyphosphates and Complement Activation

Immunomodulation of neutrophil granulocyte functions by bacterial polyphosphates

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