Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200092, China.
Nat Commun. 2022 Jul 14;13(1):4074. doi: 10.1038/s41467-022-31723-4.
Cryptococcosis is a potentially lethal disease that is primarily caused by the fungus Cryptococcus neoformans, treatment options for cryptococcosis are limited. Here, we show glucuronoxylomannan, the major polysaccharide component of C. neoformans, induces the recruitment of neutrophilic myeloid-derived suppressor cells in mice and patients with cryptococcosis. Depletion of neutrophilic myeloid-derived suppressor cells enhances host defense against C. neoformans infection. We identify C-type lectin receptor-2d recognizes glucuronoxylomannan to potentiate the immunosuppressive activity of neutrophilic myeloid-derived suppressor cells by initiating p38-mediated production of the enzyme arginase-1, which inhibits T-cell mediated antifungal responses. Notably, pharmacological inhibition of arginase-1 expression by a specific inhibitor of p38, SB202190, or an orally available receptor tyrosine kinase inhibitor, vandetanib, significantly enhances T-cell mediated antifungal responses against cryptococcosis. These data reveal a crucial suppressive role of neutrophilic myeloid-derived suppressor cells during cryptococcosis and highlight a promising immunotherapeutic application by inhibiting arginase-1 production to combat infectious diseases.
隐球菌病是一种潜在致命的疾病，主要由新型隐球菌引起，隐球菌病的治疗选择有限。在这里，我们表明，新型隐球菌的主要多糖成分葡聚糖甘露聚糖在小鼠和隐球菌病患者中诱导中性粒细胞髓源抑制细胞的募集。中性粒细胞髓源抑制细胞的耗竭增强了宿主对新型隐球菌感染的防御。我们发现 C 型凝集素受体-2d 识别葡聚糖甘露聚糖，通过启动 p38 介导的酶精氨酸酶-1 的产生，增强中性粒细胞髓源抑制细胞的免疫抑制活性，从而抑制 T 细胞介导的抗真菌反应。值得注意的是，通过 p38 的特异性抑制剂 SB202190 或口服可用的受体酪氨酸激酶抑制剂凡德他尼抑制精氨酸酶-1 的表达，可显著增强 T 细胞介导的抗隐球菌反应。这些数据揭示了中性粒细胞髓源抑制细胞在隐球菌病中的关键抑制作用，并强调了通过抑制精氨酸酶-1 的产生来抑制感染性疾病的有希望的免疫治疗应用。
