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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 COX-2+/+ and COX-2-/- mice.(A) Western blot analysis of iNOS and Arg-1 protein in extracts from hearts of COX-2+/+ and COX-2-/- from non-infected mice (0 d.p.i.) and at 14 d.p.i. Ponceau staining of the blot is shown as a loading control. Samples for 6 different infected mice are shown. (B) Quantification of iNOS and Arg-1 band areas relative to the Ponceau staining from COX-2+/+ (dashed black bars) and COX-2-/- (dashed gray bars) is represented as means ± SEM in arbitrary units. A representative experiment (n = 5) out of two is shown (**p<0.01).
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pntd.0004025.g005: iNOS and Arg-1 expression in T. cruzi infected cardiac tissue of COX-2+/+ and COX-2-/- mice.(A) Western blot analysis of iNOS and Arg-1 protein in extracts from hearts of COX-2+/+ and COX-2-/- from non-infected mice (0 d.p.i.) and at 14 d.p.i. Ponceau staining of the blot is shown as a loading control. Samples for 6 different infected mice are shown. (B) Quantification of iNOS and Arg-1 band areas relative to the Ponceau staining from COX-2+/+ (dashed black bars) and COX-2-/- (dashed gray bars) is represented as means ± SEM in arbitrary units. A representative experiment (n = 5) out of two is shown (**p<0.01).

Mentions: To characterize the immune response in hearts of COX-2-/- infected mice, gene expression of chemokines and cytokines were analyzed. mRNA levels of chemokines (Ccl2, Ccl5 and Cxcl9) and cytokines (Ifng, Tnf, Il4, Il6 and Il10) were significantly increased during T. cruzi infection in hearts of both COX-2+/+ and COX-2-/- mice (Fig 4B and 4C). However, chemokine expression presented different patterns in COX-2+/+ and COX-2-/- mice. Ccl2 and Ccl5 expression, but not Cxcl9, was significantly higher in COX-2+/+ mice than in COX-2-/- mice (Fig 4B). Induction of pro-inflammatory cytokines Ifng, Tnf and Il6 was lower, whereas Il4 expression was higher, in COX-2-/- compared to COX-2+/+ mice (Fig 4C). The anti-inflammatory cytokine Il10 showed lower expression in the COX-2-/- infected mice. There were no significant differences in Arg1 expression between COX-2+/+ or COX-2-/- mice (Fig 4D), but induction of Nos2 mRNA (iNOS) was significantly lower in COX-2-/- infected mice (Fig 4D). There was no induction of Ptgs1 (COX-1) expression that could compensate for the COX-2-/- deficiency (Fig 4D). Ptges (mPGES-1) expression was increased upon infection, with lower levels in heart tissue from COX-2-/- mice compared to COX-2+/+ mice (Fig 4D). Nevertheless, protein analysis by western blot showed lower expression of both iNOS and Arg-1 in infected COX-2-/- respect to COX-2+/+ mice (Fig 5). Analysis of TNF-α levels in plasma showed a similar increase in both COX-2+/+ and COX-2-/- infected mice, indicating that the effect of COX-2 deficiency is not systemic but specific of the heart (S3A Fig). Basal levels of gene expression did not significantly change between COX-2+/+ and COX-2-/- mice (S4 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 COX-2+/+ and COX-2-/- mice.(A) Western blot analysis of iNOS and Arg-1 protein in extracts from hearts of COX-2+/+ and COX-2-/- from non-infected mice (0 d.p.i.) and at 14 d.p.i. Ponceau staining of the blot is shown as a loading control. Samples for 6 different infected mice are shown. (B) Quantification of iNOS and Arg-1 band areas relative to the Ponceau staining from COX-2+/+ (dashed black bars) and COX-2-/- (dashed gray bars) is represented as means ± SEM in arbitrary units. A representative experiment (n = 5) out of two is shown (**p<0.01).
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Related In: Results  -  Collection

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pntd.0004025.g005: iNOS and Arg-1 expression in T. cruzi infected cardiac tissue of COX-2+/+ and COX-2-/- mice.(A) Western blot analysis of iNOS and Arg-1 protein in extracts from hearts of COX-2+/+ and COX-2-/- from non-infected mice (0 d.p.i.) and at 14 d.p.i. Ponceau staining of the blot is shown as a loading control. Samples for 6 different infected mice are shown. (B) Quantification of iNOS and Arg-1 band areas relative to the Ponceau staining from COX-2+/+ (dashed black bars) and COX-2-/- (dashed gray bars) is represented as means ± SEM in arbitrary units. A representative experiment (n = 5) out of two is shown (**p<0.01).
Mentions: To characterize the immune response in hearts of COX-2-/- infected mice, gene expression of chemokines and cytokines were analyzed. mRNA levels of chemokines (Ccl2, Ccl5 and Cxcl9) and cytokines (Ifng, Tnf, Il4, Il6 and Il10) were significantly increased during T. cruzi infection in hearts of both COX-2+/+ and COX-2-/- mice (Fig 4B and 4C). However, chemokine expression presented different patterns in COX-2+/+ and COX-2-/- mice. Ccl2 and Ccl5 expression, but not Cxcl9, was significantly higher in COX-2+/+ mice than in COX-2-/- mice (Fig 4B). Induction of pro-inflammatory cytokines Ifng, Tnf and Il6 was lower, whereas Il4 expression was higher, in COX-2-/- compared to COX-2+/+ mice (Fig 4C). The anti-inflammatory cytokine Il10 showed lower expression in the COX-2-/- infected mice. There were no significant differences in Arg1 expression between COX-2+/+ or COX-2-/- mice (Fig 4D), but induction of Nos2 mRNA (iNOS) was significantly lower in COX-2-/- infected mice (Fig 4D). There was no induction of Ptgs1 (COX-1) expression that could compensate for the COX-2-/- deficiency (Fig 4D). Ptges (mPGES-1) expression was increased upon infection, with lower levels in heart tissue from COX-2-/- mice compared to COX-2+/+ mice (Fig 4D). Nevertheless, protein analysis by western blot showed lower expression of both iNOS and Arg-1 in infected COX-2-/- respect to COX-2+/+ mice (Fig 5). Analysis of TNF-α levels in plasma showed a similar increase in both COX-2+/+ and COX-2-/- infected mice, indicating that the effect of COX-2 deficiency is not systemic but specific of the heart (S3A Fig). Basal levels of gene expression did not significantly change between COX-2+/+ and COX-2-/- mice (S4 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