The Expression profile of splenic Ly6C low/Ly6C high macrophages in SLC29A3 deficient mice
Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 lead to the accumulation of nucleosides in lysosomes and result in histiocytosis, characterized by the excessive accumulation of phagocytes in multiple organs. However, the underlying mechanism by which lysosomal nucleoside storage drives histiocytosis remains poorly understood. Herein, we provide evidence that histiocytosis in Slc29a3–/– mice is dependent on Toll-like receptor 7 (TLR7), which senses a combination of guanosines and oligoribonucleotides. TLR7 increased phagocyte populations by driving the proliferation of immature Ly6C high splenic macrophages and their subsequent maturation into Ly6C low phagocytes in Slc29a3–/– mice. Interestingly, TLR7 activation in nucleoside-laden splenic macrophages failed to induce inflammatory responses. Our data demonstrate that TLR7 responses to lysosomal nucleoside stress drive unique immune responses distinct from inflammation in SLC29A3-related disorders. Overall design: To examine the characteristics of splenic macrophages that accumulate in Slc29a3–/– mice, we isolated Ly6C low or Ly6C high splenic macrophages from wild-type/Slc29a3–/–/Slc29a3–/–TLR7–/– mice using FACS sorting. Subsequently, we performed gene expression profiling analysis by employing RNA-seq data obtained from 6 distinct macrophage samples.