Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A_2B adenosine receptor activation

Abstract

Dendritic cells (DCs) play an essential role in the modulation of immune responses and several studies have evaluated the interactions between Leishmania parasites and DCs.While extracellular ATP exhibits proinflammatory properties, adenosine is an important anti-inflammatory mediator. Here we investigated the effects of Leishmania infection on DC responses and the participation of purinergic signalling in this process. Bone marrowderived dendritic cells (BMDCs) from C57BL/6J mice infected with Leishmania amazonensis, Leishmania braziliensis or Leishmania major metacyclic promastigotes showed decreased major histocompatibility complex (MHC) class II and CD86 expression and increased ectonucleotidase expression as compared with uninfected cells. In addition, L. amazonensis-infected DCs, which had lower CD40 expression, exhibited a decreased ability to induce T-cell proliferation. The presence of MRS1754, a highly selective A 2B adenosine receptor antagonist at the time of infection increased MHC class II, CD86 and CD40 expression in L. amazonensis-infected DCs and restored the ability of the infected DCs to induce T-cell proliferation. Similar results were obtained through the inhibition of extracellular ATP hydrolysis using suramin. In conclusion, we propose that A 2B receptor activation may be used by L. amazonensis to inhibit DC function and evade the immune response. Keywords: Adenosine receptors r CD40 r Dendritic cell r Ectonucleotidases r Leishmania amazonensis IntroductionLeishmaniasis is a group of diseases that are caused by obligate intracellular parasites of the genus Leishmania. Leishmania infections can result in a wide spectrum of clinical manifestations and disease outcome is determined both by the parasite species and by Correspondence: Dr. Luís C. C. Afonso e-mail: afonso@nupeb.ufop.br the host immune response. Leishmania amazonensis differs from other species because it is able to cause chronic non-healing lesions in mouse strains genuinely resistant to other Leishmania species, such as Leishmania braziliensis and Leishmania major [1][2][3]. In humans, L. amazonensis causes diffuse cutaneous leishmaniasis, a condition characterised by a lack of antigen-specific T-cell responses against the parasite [4].DCs play a critical role in orchestrating the innate and adaptive components of the immune system [5,6]. Immature DCs capture and process antigens located throughout the body. After contacting microorganisms or other inflammatory substances, C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1204 Amanda B. Figueiredo et al. Eur. J. Immunol. 2012. 42: 1203-1215 these cells initiate their maturation process. DC maturation is characterised by increased expression of major histocompatibility complex (MHC) class II (MHCII) and co-stimulatory molecules, such as CD40, CD80, CD86 and CD54; decreased phagocytic capacity; increased cytokine secretion and expression of different chemokine receptors [5,7]. Extracellular ATP, which is accumulated following cellular injury, has important inf...

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Adenosine influences myeloid cells to inhibit aeroallergen sensitization

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Crosstalk between purinergic receptors and lipid mediators in leishmaniasis

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