Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
Microbiology (Reading). 2011 May;157(Pt 5):1416-1427. doi: 10.1099/mic.0.045989-0. Epub 2011 Feb 3.
The pathogenic fungus Cryptococcus neoformans is a major cause of morbidity and mortality in immunocompromised individuals. Infection of the human host occurs through inhalation of infectious propagules following environmental exposure. In the lung, C. neoformans can reside in the extracellular environment of the alveolar spaces or, upon phagocytosis, it can survive and grow intracellularly within alveolar macrophages (AMs). In previous studies, we found that sphingosine kinase 1 (SK1) influenced the intracellular residency of C. neoformans within AMs. Therefore, with this study we aimed to examine the role of the SK1 lipid product, sphingosine-1-phosphate (S1P), in the AMs-C. neoformans interaction. It was found that extracellular S1P enhances the phagocytosis of C. neoformans by AMs. Using both genetic and pharmacological approaches we further show that extracellular S1P exerts its effect on the phagocytosis of C. neoformans by AMs through S1P receptor 2 (S1P2). Interestingly, loss of S1P2 caused a dramatic decrease in the mRNA levels of Fcγ receptors I (FcγRI), -II and -III. In conclusion, our data suggest that extracellular S1P increases antibody-mediated phagocytosis through S1P2 by regulating the expression of the phagocytic Fcγ receptors.
新型隐球菌是一种致病性真菌，是免疫功能低下个体发病和死亡的主要原因。人类宿主通过环境暴露后吸入感染性繁殖体而感染。在肺部，新型隐球菌可以存在于肺泡腔的细胞外环境中，或者在吞噬作用后，可以在肺泡巨噬细胞（AMs）内生存和生长。在之前的研究中，我们发现鞘氨醇激酶 1（SK1）影响新型隐球菌在 AMs 内的细胞内居留。因此，在这项研究中，我们旨在研究鞘氨醇激酶 1 的脂质产物，即 1-磷酸鞘氨醇（S1P）在 AMs-新型隐球菌相互作用中的作用。结果发现细胞外 S1P 增强了 AMs 对新型隐球菌的吞噬作用。通过遗传和药理学方法，我们进一步表明，细胞外 S1P 通过 S1P 受体 2（S1P2）对 AMs 吞噬新型隐球菌的作用。有趣的是，S1P2 的缺失导致 Fcγ 受体 I（FcγRI）、-II 和 -III 的 mRNA 水平显著降低。总之，我们的数据表明，细胞外 S1P 通过调节吞噬 Fcγ 受体的表达，通过 S1P2 增加抗体介导的吞噬作用。
