TLR7/8 stress response drives histiocytosis in SLC29A3 disorders

Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3
cause lysosomal nucleoside storage and histiocytosis: phagocyte
accumulation in multiple organs. However, little is known about the
mechanism by which lysosomal nucleoside storage drives histiocytosis.
Herein, histiocytosis in Slc29a3–/– mice was shown to depend on Toll-like
receptor 7 (TLR7), which senses a combination of nucleosides and
oligoribonucleotides (ORNs). TLR7 increased phagocyte numbers by driving
the proliferation of Ly6Chi immature monocytes and their maturation into
Ly6Clow phagocytes in Slc29a3–/– mice. Downstream of TLR7, FcRγ and DAP10
were required for monocyte proliferation. Histiocytosis is accompanied by
inflammation in SLC29A3 disorders. However, TLR7 in nucleoside-laden
splenic macrophages failed to activate inflammatory responses. Enhanced
production of pro-inflammatory cytokines was observed only after
stimulation with ssRNAs, which would increase lysosomal ORNs.
Patient-derived monocytes harboring the G208R SLC29A3 mutation showed
enhanced survival and proliferation in a TLR8 antagonist-sensitive manner.
These results demonstrated that TLR7/8 responses to lysosomal nucleoside
stress drive SLC29A3 disorders.

溶酶体核苷转运蛋白SLC29A3的功能丧失型突变可引发溶酶体核苷贮积症与组织细胞增生症，表现为多器官内吞噬细胞聚集。然而，目前对于溶酶体核苷贮积驱动组织细胞增生症的具体分子机制仍知之甚少。
本研究证实，Slc29a3基因敲除（Slc29a3–/–）小鼠的组织细胞增生症依赖于Toll样受体7（Toll-like receptor 7, TLR7）——该受体可感知核苷与寡核糖核苷酸（oligoribonucleotides, ORNs）的联合信号。在Slc29a3–/–小鼠体内，TLR7通过促进Ly6C⁺幼稚单核细胞的增殖，以及其向Ly6C⁻吞噬细胞的分化成熟，增加了吞噬细胞的数量。在TLR7下游通路中，FcRγ与DAP10是单核细胞增殖所必需的调控因子。
SLC29A3相关疾病的组织细胞增生症常伴随炎症反应，但在负载核苷的脾脏巨噬细胞中，TLR7无法激活炎症应答。仅当用单链RNA（single-stranded RNA, ssRNA）刺激时，才可观察到促炎细胞因子的产生显著增加——而单链RNA可进一步提升溶酶体内寡核糖核苷酸的水平。
携带G208R突变型SLC29A3的患者来源单核细胞，其存活与增殖能力显著增强，且该效应可被TLR8拮抗剂所抑制。
上述研究结果表明，TLR7/8对溶酶体核苷应激的应答，是驱动SLC29A3相关疾病发生发展的核心机制。