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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

Parasite burden and heart inflammation in T. cruzi infected COX-2+/+ and COX-2-/- mice.(A) The presence of parasites in the blood of COX-2+/+ or COX-2-/- mice at different d.p.i. was quantified by direct counting under optical microscopy. (B) DNA from heart tissue was isolated and qPCR using T. cruzi DNA standard was performed to determine parasite burden in COX-2+/+ or COX-2-/- infected mice at 14 d.p.i. Means ± SEM from three independent experiments are shown (n = 4). (C) Heart tissue sections of COX-2+/+ and COX-2-/- mice either non-infected (0 d.p.i.) or 14 d.p.i., were stained with Masson’s Trichrome and inflammatory cell infiltration was quantified as described in Methods. (D) Representative pictures of heart tissue sections described in C. Arrows indicate inflammatory infiltration. Scale bar is 100 μm. (ns = non-significant; *p<0.05; **p< 0.01; ***p<0.001).
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pntd.0004025.g003: Parasite burden and heart inflammation in T. cruzi infected COX-2+/+ and COX-2-/- mice.(A) The presence of parasites in the blood of COX-2+/+ or COX-2-/- mice at different d.p.i. was quantified by direct counting under optical microscopy. (B) DNA from heart tissue was isolated and qPCR using T. cruzi DNA standard was performed to determine parasite burden in COX-2+/+ or COX-2-/- infected mice at 14 d.p.i. Means ± SEM from three independent experiments are shown (n = 4). (C) Heart tissue sections of COX-2+/+ and COX-2-/- mice either non-infected (0 d.p.i.) or 14 d.p.i., were stained with Masson’s Trichrome and inflammatory cell infiltration was quantified as described in Methods. (D) Representative pictures of heart tissue sections described in C. Arrows indicate inflammatory infiltration. Scale bar is 100 μm. (ns = non-significant; *p<0.05; **p< 0.01; ***p<0.001).

Mentions: In order to study the role of COX-2 in the development of cardiac leukocyte infiltration, we infected COX-2+/+ and COX-2-/- mice with the Y strain of the parasite. COX-2-/- mice showed 30% reduction in blood parasite number compared to COX-2+/+ mice at the peak of parasitemia (Fig 3A). However, COX-2 deficiency did not significantly affect cardiac parasite burden compared to COX-2+/+ infected mice (Fig 3B). No mortality was observed neither in COX-2+/+ nor in COX-2-/- infected mice up to 42 d.p.i.


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)

Parasite burden and heart inflammation in T. cruzi infected COX-2+/+ and COX-2-/- mice.(A) The presence of parasites in the blood of COX-2+/+ or COX-2-/- mice at different d.p.i. was quantified by direct counting under optical microscopy. (B) DNA from heart tissue was isolated and qPCR using T. cruzi DNA standard was performed to determine parasite burden in COX-2+/+ or COX-2-/- infected mice at 14 d.p.i. Means ± SEM from three independent experiments are shown (n = 4). (C) Heart tissue sections of COX-2+/+ and COX-2-/- mice either non-infected (0 d.p.i.) or 14 d.p.i., were stained with Masson’s Trichrome and inflammatory cell infiltration was quantified as described in Methods. (D) Representative pictures of heart tissue sections described in C. Arrows indicate inflammatory infiltration. Scale bar is 100 μm. (ns = non-significant; *p<0.05; **p< 0.01; ***p<0.001).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549243&req=5

pntd.0004025.g003: Parasite burden and heart inflammation in T. cruzi infected COX-2+/+ and COX-2-/- mice.(A) The presence of parasites in the blood of COX-2+/+ or COX-2-/- mice at different d.p.i. was quantified by direct counting under optical microscopy. (B) DNA from heart tissue was isolated and qPCR using T. cruzi DNA standard was performed to determine parasite burden in COX-2+/+ or COX-2-/- infected mice at 14 d.p.i. Means ± SEM from three independent experiments are shown (n = 4). (C) Heart tissue sections of COX-2+/+ and COX-2-/- mice either non-infected (0 d.p.i.) or 14 d.p.i., were stained with Masson’s Trichrome and inflammatory cell infiltration was quantified as described in Methods. (D) Representative pictures of heart tissue sections described in C. Arrows indicate inflammatory infiltration. Scale bar is 100 μm. (ns = non-significant; *p<0.05; **p< 0.01; ***p<0.001).
Mentions: In order to study the role of COX-2 in the development of cardiac leukocyte infiltration, we infected COX-2+/+ and COX-2-/- mice with the Y strain of the parasite. COX-2-/- mice showed 30% reduction in blood parasite number compared to COX-2+/+ mice at the peak of parasitemia (Fig 3A). However, COX-2 deficiency did not significantly affect cardiac parasite burden compared to COX-2+/+ infected mice (Fig 3B). No mortality was observed neither in COX-2+/+ nor in COX-2-/- infected mice up to 42 d.p.i.

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