O papel do Allograft Inflammatory Factor 1(AIF1) na maturação e função de Macrófagos no combate à infecção por Leishmania

Abstract

Monocytes and macrophages are the main cells against Leishmania infection. Then, these cells represent a target for immune system evasion to parasites to avoid inflammation and increase survival. Allograft Inflammatory Factor-1 (AIF1) gene is essentially expressed in myeloid lineage cells, especially dendritic cells, and macrophages. AIF1 expression can be correlated with inflammatory cascade activation to promote immune response in these cells. We observed in vitro and in vivo that Leishmania donovani infection induces a downregulation of AIF1 in spleen macrophages (7,98% ± 2.1 to 2.30%±0.6) to block the proinflammatory response and increases the intracell survival chances. Furthermore, ectopic upregulation of AIF1 in bone marrow derived macrophages can revert the immunomodulation that L.donovani infection causes in some of cytokines that is crucial to develop proinflammatory response in macrophages such as IL-6, TNF-α, Arg1 and iNOS. In addition, silencing AIF1 gene in bone marrow stem cells affects macrophages derived from monocytes development with a retention of Ly6C expression in these populations in a lack of AIF1 expression even under M-CSF stimulation. We confirmed the importance of AIF1 in bone marrow derived macrophages using am unique mouse model that presents a deletion of AIF1 gene expression in cells that express constitutively VAV1 gene, which is all kind of hematopoietic stem cells, using the LoxP/Cre system of conditional knockout of a target gene. By this, we corroborate a decrease in the numbers of monocytes and macrophages progenitors and a significant difference between both groups in the subtypes of monocytes and macrophages in the absence of AIF1 with an increase of anti-inflammatory subset Ly6C low in knockout model compared to controls. These data was corroborated in spleen samples less pronounced results as in bone marrow. Ultimately, Single Nucleotide Polymorphism (SNP) analysis was performed to evaluate the frequency of AIF1 SNP in Visceral Leishmaniasis patients and we could observe a significant higher frequency of AIF1 rs3132451 SNP mutation in endemic controls compared to patients (OR = 1.0, 67%CI =00- 00, P= 0,04) with we presumed as a genotype or resistance to Leishmania. However, rs4711274 and rs2269475 polymorphisms were significantly higher in patients’ group which configure as a genotype of susceptibility of Leishmaniasis. Together, these data support the hypotheses of an important role of AIF1 as a key-factor in the macrophages derived bone marrow cells and as an evasion pathway used to parasites as Leishmania to subvert immunity response and survive. Lastly, the presence of AIF1 polymorphisms correlation in Visceral Leishmaniasis group of patients corroborates the clinical relevance of the role AIF1 in macrophages development and function against Visceral Leishmaniasis.