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Plasmodium-induced inflammation by uric acid.

Orengo JM, Evans JE, Bettiol E, Leliwa-Sytek A, Day K, Rodriguez A - PLoS Pathog. (2008)

Bottom Line: Here we describe the molecular characterization of a novel pathway that results in the secretion of TNF by host cells.Degradation of Plasmodium-derived hypoxanthine/xanthine results in the formation of uric acid, which triggers the secretion of TNF.Identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Parasitology, New York University School of Medicine, New York, New York, USA.

ABSTRACT
Infection of erythrocytes with the Plasmodium parasite causes the pathologies associated with malaria, which result in at least one million deaths annually. The rupture of infected erythrocytes triggers an inflammatory response, which is induced by parasite-derived factors that still are not fully characterized. Induced secretion of inflammatory cytokines by these factors is considered a major cause of malaria pathogenesis. In particular, the inflammatory cytokine tumor necrosis factor (TNF) is thought to mediate most of the life-threatening pathologies of the disease. Here we describe the molecular characterization of a novel pathway that results in the secretion of TNF by host cells. We found that erythrocytes infected by Plasmodium accumulate high concentrations of hypoxanthine and xanthine. Degradation of Plasmodium-derived hypoxanthine/xanthine results in the formation of uric acid, which triggers the secretion of TNF. Since uric acid is considered a "danger signal" released by dying cells to alert the immune system, Plasmodium appears to have co-evolved to exploit this warning system. Identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.

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Related in: MedlinePlus

Uric acid induces TNF release by DCs via a MyD88 independent pathway.(A–C) DCs were incubated with medium alone (Control), the conditioned medium of uninfected erythrocytes (CM-RBCs), or the conditioned medium of P. yoelii-infected erythrocytes (CM-iRBCs) cultivated in the presence of 0.1 mg/ml uricase, 30 mM NAC or 100 U/ml catalase for 24 h. (D) Hypoxanthine concentrations were measured in the medium alone (Control), the conditioned medium of uninfected erythrocytes (CM-RBCs), or the conditioned medium of P. yoelii-infected erythrocytes (CM-iRBCs) before and after incubation with DCs in medium with serum for 24 h. (E) DCs were incubated with media alone (Control), the conditioned medium of uninfected (CM-RBC) or P. yoelii-infected (CM-iRBC) erythrocytes, 1 mg/ml monosodium urate crystals (MSU) or LPS for 24 h. (F) DCs from wild type (WT) or MyD88-/- mice were incubated with media alone (Control) the conditioned medium of uninfected (CM-RBC) or P. yoelii-infected (CM-iRBC) erythrocytes for 24 h. (A–C, E–F) Incubation media were collected and TNF or IL-1 concentrations were determined by ELISA. Data represent the average of triplicated samples with standard deviations. *P<0.05; **P<0.01.
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ppat-1000013-g005: Uric acid induces TNF release by DCs via a MyD88 independent pathway.(A–C) DCs were incubated with medium alone (Control), the conditioned medium of uninfected erythrocytes (CM-RBCs), or the conditioned medium of P. yoelii-infected erythrocytes (CM-iRBCs) cultivated in the presence of 0.1 mg/ml uricase, 30 mM NAC or 100 U/ml catalase for 24 h. (D) Hypoxanthine concentrations were measured in the medium alone (Control), the conditioned medium of uninfected erythrocytes (CM-RBCs), or the conditioned medium of P. yoelii-infected erythrocytes (CM-iRBCs) before and after incubation with DCs in medium with serum for 24 h. (E) DCs were incubated with media alone (Control), the conditioned medium of uninfected (CM-RBC) or P. yoelii-infected (CM-iRBC) erythrocytes, 1 mg/ml monosodium urate crystals (MSU) or LPS for 24 h. (F) DCs from wild type (WT) or MyD88-/- mice were incubated with media alone (Control) the conditioned medium of uninfected (CM-RBC) or P. yoelii-infected (CM-iRBC) erythrocytes for 24 h. (A–C, E–F) Incubation media were collected and TNF or IL-1 concentrations were determined by ELISA. Data represent the average of triplicated samples with standard deviations. *P<0.05; **P<0.01.

Mentions: When uricase, a specific enzyme that degrades uric acid, was added to the conditioned medium of P. yoelii-infected erythrocytes, TNF release by DCs was inhibited, confirming the role of uric acid in the observed inflammatory response (Fig. 5A). As control, we confirmed that addition of uricase did not inhibit the secretion of TNF induced by LPS (Fig. S3).


Plasmodium-induced inflammation by uric acid.

Orengo JM, Evans JE, Bettiol E, Leliwa-Sytek A, Day K, Rodriguez A - PLoS Pathog. (2008)

Uric acid induces TNF release by DCs via a MyD88 independent pathway.(A–C) DCs were incubated with medium alone (Control), the conditioned medium of uninfected erythrocytes (CM-RBCs), or the conditioned medium of P. yoelii-infected erythrocytes (CM-iRBCs) cultivated in the presence of 0.1 mg/ml uricase, 30 mM NAC or 100 U/ml catalase for 24 h. (D) Hypoxanthine concentrations were measured in the medium alone (Control), the conditioned medium of uninfected erythrocytes (CM-RBCs), or the conditioned medium of P. yoelii-infected erythrocytes (CM-iRBCs) before and after incubation with DCs in medium with serum for 24 h. (E) DCs were incubated with media alone (Control), the conditioned medium of uninfected (CM-RBC) or P. yoelii-infected (CM-iRBC) erythrocytes, 1 mg/ml monosodium urate crystals (MSU) or LPS for 24 h. (F) DCs from wild type (WT) or MyD88-/- mice were incubated with media alone (Control) the conditioned medium of uninfected (CM-RBC) or P. yoelii-infected (CM-iRBC) erythrocytes for 24 h. (A–C, E–F) Incubation media were collected and TNF or IL-1 concentrations were determined by ELISA. Data represent the average of triplicated samples with standard deviations. *P<0.05; **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2267007&req=5

ppat-1000013-g005: Uric acid induces TNF release by DCs via a MyD88 independent pathway.(A–C) DCs were incubated with medium alone (Control), the conditioned medium of uninfected erythrocytes (CM-RBCs), or the conditioned medium of P. yoelii-infected erythrocytes (CM-iRBCs) cultivated in the presence of 0.1 mg/ml uricase, 30 mM NAC or 100 U/ml catalase for 24 h. (D) Hypoxanthine concentrations were measured in the medium alone (Control), the conditioned medium of uninfected erythrocytes (CM-RBCs), or the conditioned medium of P. yoelii-infected erythrocytes (CM-iRBCs) before and after incubation with DCs in medium with serum for 24 h. (E) DCs were incubated with media alone (Control), the conditioned medium of uninfected (CM-RBC) or P. yoelii-infected (CM-iRBC) erythrocytes, 1 mg/ml monosodium urate crystals (MSU) or LPS for 24 h. (F) DCs from wild type (WT) or MyD88-/- mice were incubated with media alone (Control) the conditioned medium of uninfected (CM-RBC) or P. yoelii-infected (CM-iRBC) erythrocytes for 24 h. (A–C, E–F) Incubation media were collected and TNF or IL-1 concentrations were determined by ELISA. Data represent the average of triplicated samples with standard deviations. *P<0.05; **P<0.01.
Mentions: When uricase, a specific enzyme that degrades uric acid, was added to the conditioned medium of P. yoelii-infected erythrocytes, TNF release by DCs was inhibited, confirming the role of uric acid in the observed inflammatory response (Fig. 5A). As control, we confirmed that addition of uricase did not inhibit the secretion of TNF induced by LPS (Fig. S3).

Bottom Line: Here we describe the molecular characterization of a novel pathway that results in the secretion of TNF by host cells.Degradation of Plasmodium-derived hypoxanthine/xanthine results in the formation of uric acid, which triggers the secretion of TNF.Identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Parasitology, New York University School of Medicine, New York, New York, USA.

ABSTRACT
Infection of erythrocytes with the Plasmodium parasite causes the pathologies associated with malaria, which result in at least one million deaths annually. The rupture of infected erythrocytes triggers an inflammatory response, which is induced by parasite-derived factors that still are not fully characterized. Induced secretion of inflammatory cytokines by these factors is considered a major cause of malaria pathogenesis. In particular, the inflammatory cytokine tumor necrosis factor (TNF) is thought to mediate most of the life-threatening pathologies of the disease. Here we describe the molecular characterization of a novel pathway that results in the secretion of TNF by host cells. We found that erythrocytes infected by Plasmodium accumulate high concentrations of hypoxanthine and xanthine. Degradation of Plasmodium-derived hypoxanthine/xanthine results in the formation of uric acid, which triggers the secretion of TNF. Since uric acid is considered a "danger signal" released by dying cells to alert the immune system, Plasmodium appears to have co-evolved to exploit this warning system. Identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.

Show MeSH
Related in: MedlinePlus