Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
Immunity. 2023 Jul 11;56(7):1548-1560.e5. doi: 10.1016/j.immuni.2023.05.006. Epub 2023 Jun 5.
Cryptococcus neoformans is the leading cause of fungal meningitis and is characterized by pathogenic eosinophil accumulation in the context of type-2 inflammation. The chemoattractant receptor GPR35 is expressed by granulocytes and promotes their migration to the inflammatory mediator 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite. Given the inflammatory nature of cryptococcal infection, we examined the role of GPR35 in the circuitry underlying cell recruitment to the lung. GPR35 deficiency dampened eosinophil recruitment and fungal growth, whereas overexpression promoted eosinophil homing to airways and fungal replication. Activated platelets and mast cells were the sources of GPR35 ligand activity and pharmacological inhibition of serotonin conversion to 5-HIAA, or genetic deficiency in 5-HIAA production by platelets and mast cells resulted in more efficient clearance of Cryptococcus. Thus, the 5-HIAA-GPR35 axis is an eosinophil chemoattractant receptor system that modulates the clearance of a lethal fungal pathogen, with implications for the use of serotonin metabolism inhibitors in the treatment of fungal infections.
新型隐球菌是真菌性脑膜炎的主要病因，其特征是在 2 型炎症的背景下，嗜酸性粒细胞的病理性积累。趋化因子受体 GPR35 由粒细胞表达，并促进其向炎症介质 5-羟吲哚乙酸（5-HIAA，即血清素代谢物）迁移。鉴于隐球菌感染的炎症性质，我们研究了 GPR35 在细胞招募到肺部的通路中的作用。GPR35 缺乏会抑制嗜酸性粒细胞的募集和真菌的生长，而过表达则促进嗜酸性粒细胞向气道归巢和真菌的复制。活化的血小板和肥大细胞是 GPR35 配体活性的来源，通过药理学抑制血清素转化为 5-HIAA，或通过血小板和肥大细胞的基因缺陷来抑制 5-HIAA 的产生，可导致隐球菌的清除效率更高。因此，5-HIAA-GPR35 轴是一种嗜酸性粒细胞趋化因子受体系统，可调节致命真菌病原体的清除，这对使用血清素代谢抑制剂治疗真菌感染具有重要意义。
