Minhang Hospital, Fudan University, 170 Xinsong Road, Shanghai, 201199, China.
Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, China.
Appl Microbiol Biotechnol. 2019 Jun;103(12):4825-4838. doi: 10.1007/s00253-019-09832-w. Epub 2019 May 3.
Arginase I has been documented to impair T cell function and attenuate cellular immunity, however, there is little evidence to reveal the effect of arginase I on macrophage function. Recently, recombinant human arginase I (rhArg) has been developed for cancer therapy and is in clinical trial for hepatocellular carcinoma, whereas the potential immunosuppression induced by rhArg limited its therapeutic efficacy. To improve the clinical outcome of rhArg, addressing the immune suppression appears to be particularly important. In this study, we found that rhArg attenuated macrophage functions, including inhibiting macrophage cell proliferation, nitric oxide (NO) and reactive oxygen species (ROS) production, cytokine secretion, MHC-II surface expression, and phagocytosis, thereby inducing immunosuppression in lipopolysaccharides (LPS)/interferon-γ (IFN-γ)-activated macrophages. Notably, we observed that rhArg downregulated autophagy in activated macrophages. Moreover, application of trehalose (an autophagy inducer) significantly restored the impaired immune function in activated macrophages, suggesting the essential role of autophagy in rhArg-induced immunosuppression. To further illustrate the effect of autophagy in immunosuppression, we then observed the effect of 3-MA (an autophagy inhibitor) on the immune function of macrophages. As expected, inhibiting autophagy by 3-MA attenuated immune functions in activated macrophages. Collectively, this study elucidated that rhArg induced immunosuppression in activated macrophages via inhibiting autophagy, providing potential strategy to ameliorate the immune suppression which is of great significance to cancer therapy and facilitating the development of rhArg as a potential therapy for malignant carcinomas.
精氨酸酶 I 已被证明会损害 T 细胞功能并减弱细胞免疫，但目前几乎没有证据表明精氨酸酶 I 对巨噬细胞功能有影响。最近，重组人精氨酸酶 I（rhArg）已被开发用于癌症治疗，并正在进行肝细胞癌的临床试验，然而，rhArg 引起的潜在免疫抑制作用限制了其治疗效果。为了提高 rhArg 的临床疗效，解决免疫抑制问题似乎尤为重要。在这项研究中，我们发现 rhArg 减弱了巨噬细胞的功能，包括抑制巨噬细胞的增殖、一氧化氮（NO）和活性氧（ROS）的产生、细胞因子的分泌、MHC-II 表面表达和吞噬作用，从而在脂多糖（LPS）/干扰素-γ（IFN-γ）激活的巨噬细胞中诱导免疫抑制。值得注意的是，我们观察到 rhArg 下调了激活的巨噬细胞中的自噬。此外，应用海藻糖（一种自噬诱导剂）显著恢复了激活的巨噬细胞中受损的免疫功能，表明自噬在 rhArg 诱导的免疫抑制中起重要作用。为了进一步阐明自噬在免疫抑制中的作用，我们观察了 3-MA（一种自噬抑制剂）对巨噬细胞免疫功能的影响。不出所料，通过 3-MA 抑制自噬会减弱激活的巨噬细胞中的免疫功能。总之，这项研究阐明了 rhArg 通过抑制自噬诱导激活的巨噬细胞中的免疫抑制，为改善免疫抑制提供了潜在策略，这对于癌症治疗具有重要意义，并促进了 rhArg 作为恶性肿瘤潜在治疗方法的发展。
