Chen Wei, Ghobrial Rafik M, Li Xian C, Kloc Malgorzata
Houston Methodist Research Institute, Houston, TX, USA; Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha 410011, China.
Houston Methodist Research Institute, Houston, TX, USA; Weill Cornell Medical College, 407 E 61st St, New York, USA.
Immunobiology. 2018 Nov;223(11):634-647. doi: 10.1016/j.imbio.2018.07.009. Epub 2018 Jul 7.
Macrophage functions in the immune response depend on their ability to infiltrate tissues and organs. The penetration between and within the tissues requires degradation of extracellular matrix (ECM), a function performed by the specialized, endopeptidase- and actin filament- rich organelles located at the ventral surface of macrophage, called the podosomes. Podosome formation requires local inhibition of small GTPase RhoA activity, and depends on Rac 1/Rho guanine nucleotide exchange factor 7, β-PIX and its binding partner the p21-activated kinase (PAK-1). The activity of RhoA and Rac 1 is in turn regulated by mTOR/mTORC2 pathway. Here we showed that a fungus metabolite Fingolimod (FTY720, Gilenya), which is clinically approved for the treatment of multiple sclerosis, down-regulates Rictor, which is a signature molecule of mTORC2 and dictates its substrate (actin cytoskeleton) specificity, down-regulates RhoA, up-regulates PAK-1, and causes amplification of podosomes in mouse peritoneal macrophages.
巨噬细胞在免疫反应中的功能取决于它们浸润组织和器官的能力。在组织之间以及组织内部的穿透需要降解细胞外基质（ECM），这一功能由位于巨噬细胞腹侧表面的特殊、富含内肽酶和肌动蛋白丝的细胞器——足体来执行。足体的形成需要局部抑制小GTP酶RhoA的活性，并依赖于Rac 1/Rho鸟嘌呤核苷酸交换因子7、β-PIX及其结合伴侣p21激活激酶（PAK-1）。RhoA和Rac 1的活性又受mTOR/mTORC2途径的调节。在此我们表明，一种临床上已被批准用于治疗多发性硬化症的真菌代谢产物芬戈莫德（FTY720，Gilenya），可下调Rictor（mTORC2的标志性分子，并决定其底物（肌动蛋白细胞骨架）的特异性），下调RhoA，上调PAK-1，并导致小鼠腹腔巨噬细胞中足体的扩增。
