Leishmania donovani is known to induce myelopoiesis and to dramatically increase extramedullary myelopoiesis. This results in splenomegaly, which is then accompanied by disruption of the splenic microarchitecture, a chronic inflammatory environment, and immunosuppression. Chronically inflamed tissues are typically hypoxic. The role of hypoxia on myeloid cell functions during visceral leishmaniasis has not yet been studied. Here we show that L. donovani promotes the output from the bone marrow of monocytes with a regulatory phenotype that function as safe targets for the parasite. We also demonstrate that splenic myeloid cells acquire MDSC-like function in a HIF-1α-dependent manner. HIF-1α is also involved in driving the polarization towards M2-like macrophages and rendering intermediate stage monocytes more susceptible to L. donovani infection. Our results suggest that HIF-1α is a major player in the establishment of chronic Leishmania infection and is crucial for enhancing immunosuppressive functions and lowering leishmanicidal capacity of myeloid cells.

已知利什曼原虫donovani诱导骨髓生成并显着增加髓外骨髓生成。这导致脾肿大，然后伴随脾微结构的破坏，慢性炎症环境和免疫抑制。慢性发炎的组织通常缺氧。内脏利什曼病期间缺氧对髓样细胞功能的作用尚未研究。在这里，我们表明，大号。多诺瓦尼促进具有调节表型的单核细胞从骨髓的输出，该表型可作为寄生虫的安全靶标。我们还证明了脾髓样细胞以HIF-1α依赖的方式获得MDSC样功能。HIF-1α还参与驱动极化朝着M2样巨噬细胞的方向移动，并使中级单核细胞更易受L的影响。donovani感染。我们的结果表明，HIF-1α在建立慢性利什曼原虫感染中起主要作用，并且对于增强免疫抑制功能和降低髓样细胞的利什曼杀菌能力至关重要。