Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
Parasite Immunol. 2013 Dec;35(12):409-20. doi: 10.1111/pim.12049.
Leishmania major is an aetiological agent of cutaneous leishmaniasis. The parasite primarily infects immune sentinel cells, specifically macrophages and dendritic cells, in the mammalian host. Infection is receptor mediated and is known to involve parasite binding to cell surface protein complement receptor 3 (CR3, Mac-1, CD11b/CD18). Engagement of CR3 by various ligands inhibits production of interleukin-12 (IL-12), the cytokine that drives antileishmanial T helper 1-type immune responses. Likewise, L. major infection inhibits IL-12 production and activation of host macrophages. Our data indicate that in the absence of CR3, L. major-infected bone marrow-derived macrophages produce more IL-12 and nitric oxide compared with WT cells upon lipopolysaccharide (LPS) stimulation. We therefore investigated multiple signalling pathways by which L. major may inhibit IL-12 transcription through CR3 ligation. We demonstrate that L. major infection does not elicit significant NFκB p65, MAPK, IRF-1 or IRF-8 activation in WT or CD11b-deficient macrophages. Furthermore, infection neither inhibits LPS-induced MAPK or NFκB activation nor blocks IFN-γ-activated IRF-1 and IRF-8. ETS-mediated transcription, however, is inhibited by L. major infection independently of CR3. Our data indicate that L. major-mediated inhibition of IL-12 occurs through CR3 engagement; however, the mechanism of inhibition is independent of NFκB, MAPK, IRF and ETS.
利什曼原虫是皮肤利什曼病的病原体。寄生虫主要感染哺乳动物宿主中的免疫哨兵细胞，特别是巨噬细胞和树突状细胞。感染是受体介导的，已知涉及寄生虫与细胞表面蛋白补体受体 3（CR3，Mac-1，CD11b/CD18）结合。各种配体与 CR3 的结合抑制白细胞介素-12（IL-12）的产生，IL-12 是驱动抗利什曼原虫 T 辅助 1 型免疫反应的细胞因子。同样，L. major 感染抑制 IL-12 的产生和宿主巨噬细胞的激活。我们的数据表明，在没有 CR3 的情况下，与 WT 细胞相比，L. major 感染的骨髓来源巨噬细胞在脂多糖（LPS）刺激下产生更多的 IL-12 和一氧化氮。因此，我们研究了多种信号通路，通过这些信号通路，L. major 可能通过 CR3 结合抑制 IL-12 的转录。我们证明，L. major 感染不会在 WT 或 CD11b 缺陷型巨噬细胞中引发显著的 NFκB p65、MAPK、IRF-1 或 IRF-8 激活。此外，感染既不抑制 LPS 诱导的 MAPK 或 NFκB 激活，也不阻断 IFN-γ 激活的 IRF-1 和 IRF-8。然而，ETS 介导的转录被 L. major 感染抑制，而与 CR3 无关。我们的数据表明，L. major 介导的 IL-12 抑制是通过 CR3 结合发生的；然而，抑制的机制独立于 NFκB、MAPK、IRF 和 ETS。
