Nucleosides drive histiocytosis in SLC29A3 disorders by activating TLR7

Abstract

A lysosomal transmembrane protein SLC29A3 transports nucleosides from lysosomes to the cytoplasm. Loss-of-function mutations of the SLC29A3 gene cause lysosomal nucleoside storage in monocyte/macrophages, leading to their accumulation called histiocytosis in humans and mice. Little is known, however, about a mechanism behind nucleoside-dependent histiocytosis. TLR7, an innate immune sensors for single stranded RNA, bind and respond to nucleosides. We here show that they drive nucleoside-mediated histiocytosis. Patrolling monocyte/macrophages accumulate in the spleen of Slc29a3 -/mice but not Slc29a3 -/-Tlr7 -/mice. Accumulated patrolling monocyte/macrophages stored nucleosides derived from cell corpse. TLR7 was recruited to phagosomes and activated as evidenced by TLR7-dependent phagosomal maturation. TLR7 induced hyper-responsiveness to M-CSF in Slc29a3 -/monocyte/macrophages. These results suggest that TLR7 drives histiocytosis in SLC29A3 disorders.One Sentence Summary: SLC29A3 disorders are caused by activation of TLR7 with accumulated nucleosides in lysosomes. Main Text:Our recent results revealed an unexpected link between Toll-like receptors (TLRs) and some forms of histiocytosis, a disease characterized by expansion of dendritic cells or monocyte/macrophages (1, 2). TLRs serve as pathogen sensors in monocytes and

Regulation of the nucleic acid-sensing Toll-like receptors

“…One clear example of this principle comes from recent preprint data of mice lacking SLC29A3, a member of the solute carrier family that functions to maintain nucleoside homeostasis. These mice accumulate endosomal nucleosides and develop disease with many of the hallmarks observed in other models of TLR7 dysregulation 79 . SLC29A3-deficient mice and humans have other abnormalities, most likely related to altered nucleoside homeostasis [80][81][82][83] , but much of the autoimmune pathology in mice is rescued by TLR7 deficiency 79 .…”

“…These mice accumulate endosomal nucleosides and develop disease with many of the hallmarks observed in other models of TLR7 dysregulation 79 . SLC29A3-deficient mice and humans have other abnormalities, most likely related to altered nucleoside homeostasis [80][81][82][83] , but much of the autoimmune pathology in mice is rescued by TLR7 deficiency 79 . This example further illustrates how fundamental homeostatic mechanisms contribute to the carefully balanced recognition system of endosomal TLRs.…”

Regulatory strategies limiting endosomal Toll‐like receptor activation in B cells*

“…Although transgenic RNAse A overexpression protects against the development of TLR7‐driven murine SLE, 40 this limited phenotype of RNAse enzyme knockout strains suggests either functional redundancy across RNAse enzymes or the existence of alternate mechanisms to limit RNA accumulation. In keeping with this latter hypothesis, mutations in Slc29a3 , a lysosomal transporter that traffics nucleoside from lysosomes to the cytoplasm, promote TLR7‐dependent histiocytosis in mice 41 . Although the predominant clinical phenotypes of human SLC29A3 deficiency include monogenic histiocytic disorders such as H syndrome and familial Rosai‐Dorfman disease, 42,43 rather than SLE, an intronic polymorphism in SLC29A3 that limited monocyte expression was recently identified in an Asian lupus cohort 44 .…”

“…In keeping with this latter hypothesis, mutations in Slc29a3, a lysosomal transporter that traffics nucleoside from lysosomes to the cytoplasm, promote TLR7-dependent histiocytosis in mice. 41 Although the predominant clinical phenotypes of human SLC29A3 deficiency include monogenic histiocytic disorders such as H syndrome and familial Rosai-Dorfman disease, 42,43 rather than SLE, an intronic polymorphism in SLC29A3 that limited monocyte expression was recently identified in an Asian lupus cohort. 44 Thus, rather than RNA degradation, nucleoside removal from the endolysosomal compartment may be the dominant mechanism limiting inadvertent TLR7 engagement.…”

Shaping the Innate Immune Response Through Post-Transcriptional Regulation of Gene Expression Mediated by RNA-Binding Proteins

“…RNAse T2 is seemingly required for activation of TLR7 in macrophages ( 88 ) and crystallography studies suggest that successive U-containing ssRNA sequences are required for full binding to TLR7 ( 89 ). Studies in macrophages moreover suggested that accumulation of nucleosides in the lysosomal compartment upon inactivation of the lysosomal transmembrane protein SLC29A3 (a nucleoside transporter from lysosomes to the cytoplasm) leads to TLR7 activation following phagocytosis of necrotic cells ( 90 ). Interestingly, in monocytes, macrophages, and dendritic cells, the accumulation of nucleosides within lysosomes is responsible for inflammatory disorders like histiocytosis, further emphasizing the importance of a tight control of RNA mediated TLR activation ( 91 ).…”