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Cyclooxygenase-2 and Prostaglandin E2 Signaling through Prostaglandin Receptor EP-2 Favor the Development of Myocarditis during Acute Trypanosoma cruzi Infection.

Guerrero NA, Camacho M, Vila L, Íñiguez MA, Chillón-Marinas C, Cuervo H, Poveda C, Fresno M, Gironès N - PLoS Negl Trop Dis (2015)

Bottom Line: Our results show an increase in the expression of several of these enzymes in acute T. cruzi infected heart.T. cruzi infections in COX-2 or PGE2-dependent prostaglandin receptor EP-2 deficient mice indicate that both, COX-2 and EP-2 signaling contribute significantly to the heart leukocyte infiltration and to the release of chemokines and inflammatory cytokines in the heart of T. cruzi infected mice.In conclusion, COX-2 plays a detrimental role in acute Chagas disease myocarditis and points to COX-2 as a potential target for immune intervention.

View Article: PubMed Central - PubMed

Affiliation: Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.

ABSTRACT
Inflammation plays an important role in the pathophysiology of Chagas disease, caused by Trypanosoma cruzi. Prostanoids are regulators of homeostasis and inflammation and are produced mainly by myeloid cells, being cyclooxygenases, COX-1 and COX-2, the key enzymes in their biosynthesis from arachidonic acid (AA). Here, we have investigated the expression of enzymes involved in AA metabolism during T. cruzi infection. Our results show an increase in the expression of several of these enzymes in acute T. cruzi infected heart. Interestingly, COX-2 was expressed by CD68+ myeloid heart-infiltrating cells. In addition, infiltrating myeloid CD11b+Ly6G- cells purified from infected heart tissue express COX-2 and produce prostaglandin E2 (PGE2) ex vivo. T. cruzi infections in COX-2 or PGE2-dependent prostaglandin receptor EP-2 deficient mice indicate that both, COX-2 and EP-2 signaling contribute significantly to the heart leukocyte infiltration and to the release of chemokines and inflammatory cytokines in the heart of T. cruzi infected mice. In conclusion, COX-2 plays a detrimental role in acute Chagas disease myocarditis and points to COX-2 as a potential target for immune intervention.

No MeSH data available.


Related in: MedlinePlus

iNOS and Arg-1 expression in T. cruzi infected cardiac tissue of EP-2+/+ and EP-2-/- mice.(A) Western blot analysis of iNOS and Arg-1 protein in extracts from hearts of EP-2+/+ and EP-2-/- non-infected mice (0 d.p.i.) and at 14 d.p.i. Ponceau staining of the blot is shown as a loading control. Extracts from 3 different infected mice were loaded. (B) Quantification of iNOS and Arg-1 band areas relative to the Ponceau staining from EP-2+/+ (black bars) and EP-2-/- (gray bars) is represented as means ± SEM in arbitrary units. A representative experiment out of two is shown (**p<0.01; ***p<0.001).
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pntd.0004025.g008: iNOS and Arg-1 expression in T. cruzi infected cardiac tissue of EP-2+/+ and EP-2-/- mice.(A) Western blot analysis of iNOS and Arg-1 protein in extracts from hearts of EP-2+/+ and EP-2-/- non-infected mice (0 d.p.i.) and at 14 d.p.i. Ponceau staining of the blot is shown as a loading control. Extracts from 3 different infected mice were loaded. (B) Quantification of iNOS and Arg-1 band areas relative to the Ponceau staining from EP-2+/+ (black bars) and EP-2-/- (gray bars) is represented as means ± SEM in arbitrary units. A representative experiment out of two is shown (**p<0.01; ***p<0.001).

Mentions: However, significant less heart inflammatory infiltrates were observed in infected EP-2-/- in comparison with EP-2+/+ mice at 14 d.p.i. (Fig 6D). Representative images of cardiac tissue and inflammatory infiltration are shown in Fig 6E. The expression of the common leukocyte marker Ptprc (CD45) was lower in the heart of infected EP-2-/- mice respect to EP-2+/+, whereas mRNA levels of cell markers as Cd4 (Th cells), Cd8 (Tc cells), and Itgax- (CD11c; DCs), did not show significant differences. However, the expression of Cd68, a macrophage marker, significantly increased in EP-2-/- respect to EP-2+/+ mice (Fig 7A). Regarding chemokines, Ccl2 expression, but not Ccl5 and Cxcl9, was significantly reduced in the EP-2-/- compared to EP-2+/+ infected mice (Fig 7B). Induction of pro-inflammatory cytokines Ifng and Il6, the Th2 cytokine Il4 and the anti-inflammatory cytokine Il10, but not Tnf, was lower in EP-2-/- compared with EP-2+/+ (Fig 7C). Similarly to COX-2-/-, no differences were observed in TNF-α plasma levels in EP-2-/- as compared to EP-2+/+ infected mice (S3B Fig). Ptgs2 (COX-2) gene expression was significantly lower in EP-2-/- infected mice (Fig 7D). There were no differences between mouse strains in Nos2 mRNA (iNOS) expression (Fig 7D), but Arg1 mRNA expression was higher in EP-2-/- mice (Fig 7D). Western blot analysis showed a significant increase in EP-2-/- respect to EP-2+/+ mice, in the protein levels of these enzymes involved in L-arginine metabolism (Fig 8). Basal levels of gene expression did not significantly change between EP-2+/+ and EP-2-/- mice (S5 Fig).


Cyclooxygenase-2 and Prostaglandin E2 Signaling through Prostaglandin Receptor EP-2 Favor the Development of Myocarditis during Acute Trypanosoma cruzi Infection.

Guerrero NA, Camacho M, Vila L, Íñiguez MA, Chillón-Marinas C, Cuervo H, Poveda C, Fresno M, Gironès N - PLoS Negl Trop Dis (2015)

iNOS and Arg-1 expression in T. cruzi infected cardiac tissue of EP-2+/+ and EP-2-/- mice.(A) Western blot analysis of iNOS and Arg-1 protein in extracts from hearts of EP-2+/+ and EP-2-/- non-infected mice (0 d.p.i.) and at 14 d.p.i. Ponceau staining of the blot is shown as a loading control. Extracts from 3 different infected mice were loaded. (B) Quantification of iNOS and Arg-1 band areas relative to the Ponceau staining from EP-2+/+ (black bars) and EP-2-/- (gray bars) is represented as means ± SEM in arbitrary units. A representative experiment out of two is shown (**p<0.01; ***p<0.001).
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Related In: Results  -  Collection

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pntd.0004025.g008: iNOS and Arg-1 expression in T. cruzi infected cardiac tissue of EP-2+/+ and EP-2-/- mice.(A) Western blot analysis of iNOS and Arg-1 protein in extracts from hearts of EP-2+/+ and EP-2-/- non-infected mice (0 d.p.i.) and at 14 d.p.i. Ponceau staining of the blot is shown as a loading control. Extracts from 3 different infected mice were loaded. (B) Quantification of iNOS and Arg-1 band areas relative to the Ponceau staining from EP-2+/+ (black bars) and EP-2-/- (gray bars) is represented as means ± SEM in arbitrary units. A representative experiment out of two is shown (**p<0.01; ***p<0.001).
Mentions: However, significant less heart inflammatory infiltrates were observed in infected EP-2-/- in comparison with EP-2+/+ mice at 14 d.p.i. (Fig 6D). Representative images of cardiac tissue and inflammatory infiltration are shown in Fig 6E. The expression of the common leukocyte marker Ptprc (CD45) was lower in the heart of infected EP-2-/- mice respect to EP-2+/+, whereas mRNA levels of cell markers as Cd4 (Th cells), Cd8 (Tc cells), and Itgax- (CD11c; DCs), did not show significant differences. However, the expression of Cd68, a macrophage marker, significantly increased in EP-2-/- respect to EP-2+/+ mice (Fig 7A). Regarding chemokines, Ccl2 expression, but not Ccl5 and Cxcl9, was significantly reduced in the EP-2-/- compared to EP-2+/+ infected mice (Fig 7B). Induction of pro-inflammatory cytokines Ifng and Il6, the Th2 cytokine Il4 and the anti-inflammatory cytokine Il10, but not Tnf, was lower in EP-2-/- compared with EP-2+/+ (Fig 7C). Similarly to COX-2-/-, no differences were observed in TNF-α plasma levels in EP-2-/- as compared to EP-2+/+ infected mice (S3B Fig). Ptgs2 (COX-2) gene expression was significantly lower in EP-2-/- infected mice (Fig 7D). There were no differences between mouse strains in Nos2 mRNA (iNOS) expression (Fig 7D), but Arg1 mRNA expression was higher in EP-2-/- mice (Fig 7D). Western blot analysis showed a significant increase in EP-2-/- respect to EP-2+/+ mice, in the protein levels of these enzymes involved in L-arginine metabolism (Fig 8). Basal levels of gene expression did not significantly change between EP-2+/+ and EP-2-/- mice (S5 Fig).

Bottom Line: Our results show an increase in the expression of several of these enzymes in acute T. cruzi infected heart.T. cruzi infections in COX-2 or PGE2-dependent prostaglandin receptor EP-2 deficient mice indicate that both, COX-2 and EP-2 signaling contribute significantly to the heart leukocyte infiltration and to the release of chemokines and inflammatory cytokines in the heart of T. cruzi infected mice.In conclusion, COX-2 plays a detrimental role in acute Chagas disease myocarditis and points to COX-2 as a potential target for immune intervention.

View Article: PubMed Central - PubMed

Affiliation: Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.

ABSTRACT
Inflammation plays an important role in the pathophysiology of Chagas disease, caused by Trypanosoma cruzi. Prostanoids are regulators of homeostasis and inflammation and are produced mainly by myeloid cells, being cyclooxygenases, COX-1 and COX-2, the key enzymes in their biosynthesis from arachidonic acid (AA). Here, we have investigated the expression of enzymes involved in AA metabolism during T. cruzi infection. Our results show an increase in the expression of several of these enzymes in acute T. cruzi infected heart. Interestingly, COX-2 was expressed by CD68+ myeloid heart-infiltrating cells. In addition, infiltrating myeloid CD11b+Ly6G- cells purified from infected heart tissue express COX-2 and produce prostaglandin E2 (PGE2) ex vivo. T. cruzi infections in COX-2 or PGE2-dependent prostaglandin receptor EP-2 deficient mice indicate that both, COX-2 and EP-2 signaling contribute significantly to the heart leukocyte infiltration and to the release of chemokines and inflammatory cytokines in the heart of T. cruzi infected mice. In conclusion, COX-2 plays a detrimental role in acute Chagas disease myocarditis and points to COX-2 as a potential target for immune intervention.

No MeSH data available.


Related in: MedlinePlus