Abstract
Adenosine is an endogenously released purine nucleoside that signals through four widely expressed G protein-coupled receptors: A1, A2A, A2B, and A3. Of these, A2AR is recognized as mediating major adenosine anti-inflammatory activity. During cutaneous leishmaniasis, adenosine induces immunosuppression, which promotes the establishment of infection. Herein, we demonstrated that A2AR signaling is exploited by Leishmania infantum parasites, the etiologic agent that causes Visceral Leishmaniasis, to successfully colonize the vertebrate host. A2AR gene-deleted mice exhibited a well-developed cellular reaction with a strong Th1 immune response in the parasitized organs. An intense infiltration of activated neutrophils into the disease-target organs was observed in A2AR−/− mice. These cells were characterized by high expression of CXCR2 and CD69 on their cell surfaces and increased cxcl1 expression. Interestingly, this phenotype was mediated by IFN-γ on the basis that a neutralizing antibody specific to this cytokine prevented neutrophilic influx into parasitized organs. In evaluating the immunosuppressive effects, we identified a decreased number of CD4+ FOXP3+ T cells and reduced il10 expression in A2AR−/− infected mice. During ex vivo cell culture, A2AR−/− splenocytes produced smaller amounts of IL-10. In conclusion, we demonstrated that the A2AR signaling pathway is detrimental to development of Th1-type adaptive immunity and that this pathway could be associated with the regulatory process. In particular, it promotes parasite surveillance.
Highlights
Leishmania parasites are the etiological agent of a wide spectrum of diseases in mammals and other vertebrates [1]
To investigate the relevance of A2AR in the course of L. infantum infection, A2AR−/− mice and control littermates were intravenously infected with 107 promastigote forms of L. infantum, and the parasite loads in the spleens and livers were quantified at various times after the infection
These data demonstrated that activation of A2AR results in the failure of BALB/c mice to control the L. infantum infection possibly due to the generation of a weaker cellular immune response
Summary
Leishmania parasites are the etiological agent of a wide spectrum of diseases in mammals and other vertebrates [1] Among this complex of diseases, Visceral Leishmaniasis (VL), which is caused by L. donovani or L. infantum, is one of the most severe clinical manifestations of infection with Leishmania parasites and is a major cause of human mortality and morbidity worldwide [2,3,4]. The most effective mechanisms for protection against Leishmania involve the generation of CD4+ Th1 cells These cells secrete IFN-γ, which activates phagocytic cells, such as neutrophils, macrophages, and dendritic cells (DCs), to release reactive oxygen species (ROS) and nitric oxide (NO). These mediators lead to the death of the parasites [5, 6]. The mechanisms that are altered could involve those mediated by cellular response [i.e., Th2 subset, regulatory T cells (Tregs)], anti-inflammatory cytokines (IL-10, TGF-β), and some metabolites that have a high capacity to inhibit leukocyte migration and activation [8], including arachidonic acid metabolites (Prostaglandins E and J series) and adenosine [9, 10]
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