Abstract
Differently from others Leishmania species, infection by the protozoan parasite L. amazonensis is associated with a lack of antigen-specific T-cell responses. Dendritic cells (DC) are essential for the innate immune response and for directing the differentiation of T-helper lymphocytes. Previously, we showed that L. amazonensis infection impairs DC activation through the activation of adenosine A2B receptor, and here, we evaluated the intracellular events triggered by this receptor in infected cells. To this aim, bone marrow-derived DC from C57BL/6J mice were infected with metacyclic promastigotes of L. amazonensis. Our results show, for the first time, that L. amazonensis increases the production of cAMP and the phosphorylation of extracellular signal-regulated protein kinases 1/2 (ERK1/2) in infected DC by a mechanism dependent on the A2B receptor. Furthermore, L. amazonensis impairs CD40 expression and IL-12 production by DC, and the inhibition of adenylate cyclase, phosphoinositide 3-kinase (PI3K), and ERK1/2 prevent these effects. The increase of ERK1/2 phosphorylation and the inhibition of DC activation by L. amazonensis are independent of protein kinase A (PKA). In addition, C57BL/6J mice were inoculated in the ears with metacyclic promastigotes, in the presence of PSB1115, an A2B receptor antagonist. PSB1115 treatment increases the percentage of CD40+ DC on ears and draining lymph nodes. Furthermore, this treatment reduces lesion size and tissue parasitism. Lymph node cells from treated mice produce higher levels of IFN-γ than control mice, without altering the production of IL-10. In conclusion, we suggest a new pathway used by the parasite (A2B receptor → cAMP → PI3K → ERK1/2) to suppress DC activation, which may contribute to the decrease of IFN-γ production following by the deficiency in immune response characteristic of L. amazonensis infection.
Highlights
Leishmania parasites are protozoa transmitted between their hosts by female sand flies and cause in humans a group of diseases known as leishmaniasis
To evaluate the accumulation of cAMP, Dendritic cells (DC) were infected with L. amazonensis, in the presence or absence of MRS1754, a selective A2B receptor antagonist, and cAMP levels measured by a chemiluminescence assay before and after the addition of 5’-(N-ethylcarboxamido) adenosine (NECA), a non-selective adenosine receptor agonist
To confirm that cAMP production induced by A2B receptor activation is important for the inhibition of DC activation by L. amazonensis, we evaluated the expression of CD40 and the production of IL-12p70 and IL-10 in cells treated with SQ22536, an inhibitor of adenylate cyclase
Summary
Leishmania parasites are protozoa transmitted between their hosts by female sand flies and cause in humans a group of diseases known as leishmaniasis. These diseases present a wide spectrum of clinical manifestations dependent on the parasite species and the host immune response. Leishmania amazonensis (L. amazonensis), in humans, causes diffuse leishmaniasis that is associated with diffuse non-ulcerative lesions with innumerous parasites. In this case, the parasite resistance to treatment is common [1, 2]. The murine model has been extensively used to evaluate the mechanisms involved in the activation/evasion of the host immune response by the parasite
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