Polyphosphates and Complement Activation

Conway, Edward M.

doi:10.3389/fmed.2019.00067

Cited by 11 publications

(8 citation statements)

References 81 publications

(78 reference statements)

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“…50,51 Only for the long-chain polyP polymers, a modulating effect on blood coagulation and innate immunity has been reported. 7,52 Results on the role of short-chain polyP have been published for the first time only recently. 53 In this report, it has been shown that polyP acts on both macrophage and fibrocyte differentiation.…”

Section: Papermentioning

confidence: 99%

The biomaterial polyphosphate blocks stoichiometric binding of the SARS-CoV-2 S-protein to the cellular ACE2 receptor

et al. 2020

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Section: Papermentioning

confidence: 99%

The biomaterial polyphosphate blocks stoichiometric binding of the SARS-CoV-2 S-protein to the cellular ACE2 receptor

et al. 2020

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“…Complement activation plays an important part in the host response to pathogens. Polyphosphates have been suggested to suppress the complement pathway (7, 29), although this mechanism has not been clearly elucidated. Elevated expression of the complement-derived anaphylatoxin, C5a, and interaction with its receptor, C5aR1, drive the pathophysiology of ALI (16, 17, 19).…”

Section: Resultsmentioning

confidence: 99%

Bacterial Polyphosphates Induce CXCL4 and Synergize with Complement Anaphylatoxin C5a in Lung Injury

Roewe

Walachowski

Sharma

et al. 2022

Preprint

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Polyphosphates are linear polymers of inorganic phosphates that exist in all living cells and serve pleiotropic functions. Bacteria produce long-chain polyphosphates, which can interfere with host defense to infection. In contrast, short-chain polyphosphates are released from platelet dense granules and bind to the chemokine, CXCL4. Here, we report that long-chain polyphosphates induced the release of CXCL4 from mouse bone marrow-derived macrophages and peritoneal macrophages in a dose-/time-dependent fashion resulting from an induction of CXCL4 mRNA. This polyphosphate effect was lost after pre-incubation with recombinant exopolyphosphatase (PPX) Fc fusion protein, demonstrating the potency of long chains over monophosphates and ambient cations. In detail, polyphosphate chains longer than 70 inorganic phosphate residues were typically required to mediate robust CXCL4 release. Polyphosphates acted independently of the purinergic P2Y1 receptor and the MyD88 and TRIF adaptors of Toll-like receptors. On the other hand, polyphosphates augmented LPS/MyD88-induced CXCL4 release, which was explained by intracellular signaling convergence on PI3K/Akt. Polyphosphates alone induced phosphorylation of Akt at threonine-308. Pharmacologic blockade of PI3K (wortmannin, LY294002) antagonized polyphosphate-induced CXCL4 release from macrophages. Intra-tracheal polyphosphate administration to C57BL/6J mice caused histologic signs of lung injury, disruption of the endothelial-epithelial barrier, influx of Ly6G+ polymorphonuclear neutrophils, depletion of CD11c+SiglecF+ alveolar macrophages, and release of CXCL4. Long-chain polyphosphates synergized with the complement anaphylatoxin, C5a, which was partly explained by upregulation of the receptor, C5aR1, on myeloid cells. C5aR1-/- mice were protected from polyphosphate-induced lung injury. In conclusion, we demonstrate that polyphosphates govern immunomodulation in macrophages and are capable of inducing lung injury.

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“…As described above, the possible anti-inflammatory effects of polyP, which are thought to be mediated through the suppression of the complement system, are discussed ( 53 , 54 ). However, the conflicting possibility that polyP has the potential to induce thrombosis should be noted.…”

Section: Discussionmentioning

confidence: 99%

Effects of SARS‑CoV‑2 mRNA vaccines on platelet polyphosphate levels and inflammation: A pilot study

et al. 2022

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Platelets function as immune cells in conjunction with white blood cells, targeting invading pathogens and inducing immune reactions. Intercellular communications among these immune cells are partly mediated by platelet polyphosphate (polyP), which was originally recognized as a thrombotic and hemostatic biomolecule. To determine the involvement of polyP in SARS-CoV-2-mRNA vaccine-induced immune responses, specifically in inflammatory responses, the effects of mRNA vaccines on platelet polyP levels were examined. Before and after vaccination with the COVID-19 vaccine (BNT162b2), blood samples were obtained from healthy, non-smoking individuals who did not have any systemic diseases. Test group demographics skewed somewhat towards either older males (first vaccination, n=6; second vaccination, n=8) or younger females (first vaccination, n=14; second vaccination, n=23). polyP levels in washed platelets from the blood samples were determined using the fluorometric method with DAPI. The side-effects of vaccination were recorded as scores. In the female group, platelet polyP levels decreased after the first vaccination, and the side-effect score increased after the second vaccination. Moderate correlation coefficients were observed between the reduction in polyP levels and the side-effect scores and pre-vaccination polyP levels. Despite the small sample size, this pilot study suggests that platelet polyP may suppress the side effects induced by the mRNA vaccines after the first vaccination, but not the second vaccination in younger female subjects, who generally have higher immune responsiveness than their male counterparts.

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Polyphosphates and Complement Activation

Cited by 11 publications

References 81 publications

The biomaterial polyphosphate blocks stoichiometric binding of the SARS-CoV-2 S-protein to the cellular ACE2 receptor

The biomaterial polyphosphate blocks stoichiometric binding of the SARS-CoV-2 S-protein to the cellular ACE2 receptor

Bacterial Polyphosphates Induce CXCL4 and Synergize with Complement Anaphylatoxin C5a in Lung Injury

Effects of SARS‑CoV‑2 mRNA vaccines on platelet polyphosphate levels and inflammation: A pilot study

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