Susceptibility or resistance to Leishmania infection is dictated by the macrophages evolved under the influence of IL-3 or GM-CSF

Abstract

Although enhanced monocytopoiesis is a hallmark of leishmaniasis, its significance in determining the course of the disease has not been addressed. While the number of granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting cells increases in the draining lymph nodes in a resistant mouse strain (C57BL/6) during disease, in a susceptible strain (BALB/c) the number of interleukin-3 (IL-3)-secreting cells increases. Treatment of BALB/c mice with anti-IL-3 antibody significantly reduces the disease score. Bone marrow macrophages derived under stimulation with IL-3 (IL-3-MΦ) or GM-CSF (GM-MΦ) differ functionally. GM-MΦ are significantly more responsive to IFN-γ-induced augmentation and more refractory to IL-4-mediated suppression of anti-leishmanial activity than IL-3-MΦ. LPS-induced IL-12 and TNF-α secretion by both the susceptible and resistant strain-derived macrophage subsets are down-regulated. Despite down-regulation of IL-12 secretion, GM-MΦ favor expansion of IFN-γ-secreting cells and IL-3-MΦ favor IL-6-dependent expansion of the IL-4-secreting Th subset. Adoptive transfer of leishmanial antigen-pulsed IL-3-MΦ and GM-MΦ prior to infection either aggravated or reduced the disease score, respectively in BALB/c mice. Anti-IL-6 treatment revelled the Th subset profile not only in vitro but also in vivo, resulting in a reduced disease score in both infected BALB/c mice and IL-3-MΦ recipients. The disease score in IL-3-MΦ recipients is also reduced significantly after anti-IL-4 treatment.