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

Date Published: August 25, 2015

Publisher: Public Library of Science

Author(s): Néstor A. Guerrero, Mercedes Camacho, Luis Vila, Miguel A. Íñiguez, Carlos Chillón-Marinas, Henar Cuervo, Cristina Poveda, Manuel Fresno, Núria Gironès, Herbert B. Tanowitz.

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.

Partial Text: Chagas disease is a multisystemic disorder caused by Trypanosoma cruzi infection that affects more than 8 million people worldwide, being endemic in Latin America. Due to the scarcity of preventive and therapeutic tools and population at risk, it is considered as a neglected tropical disease [1, 2]. More than 40,000 new infected people and 12,550 deaths per year are estimated. The high rate of migration towards non-endemic countries has spread the boundaries of the infection to other continents. Non-vectorial transmission is possible through oral ingestion, blood transfusion, organ transplantation and during pregnancy. The risk of infection is related to the country of origin of the migrants and the rate of prevalence in a given country [3].

In order to clarify the role of prostanoids in the outcome of T. cruzi infection we first analyzed the expression of prostanoid-synthesizing enzymes in cardiac tissue from T. cruzi susceptible (BALB/c) and non-susceptible (C57BL/6) mice. Our results showed an increase of COX-2/mPGES-1/PGE2 axis in heart tissue upon infection in both strains of mice, indicating that it has no direct effect on susceptibility to infection. Confocal microscopy analysis showed the presence of CD68+Arg-1+COX-2- cells and CD68+Arg-1-COX-2+, suggesting that there are at least two subpopulations of monocytic infiltrating cells with mutually exclusive expression of those enzymes. Thus, our results show that the myeloid population infiltrating the heart in T. cruzi infection is more complex than previously described [7], and suggests a difference in the function of these two myeloid populations. Macrophages can rapidly change their phenotype and function in response to local microenvironmental signals, playing key roles in the initiation and resolution of inflammation and tissue homeostasis [42] and could be involved in tissue repair and fibrosis [43]. Thus, myeloid cardiac infiltration could inhibit parasite replication and also facilitate the repair of damaged muscular tissue [44]. A suggestive hypothesis is that COX-2 expressing macrophages could be linked to inflammation meanwhile Arg-1+ macrophages could be involved in tissue repair.



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