Proposed model of the molecular mechanism driving histiocytosis and inflammation in H syndrome. In wild-type (WT) monocytes, nucleosides derived from phagocytosed cells, are exported from the endolysosome to the cytoplasm via ENT3. In H syndrome monocytes, lack of proper ENT3 function leads to accumulation of nucleosides inside endolysosomes, inducing persistent activation of TLR7/8 signaling. TLR7/8 drive downstream activation of MEK and ERK, inducing inflammatory cytokine secretion and histiocytosis. Created with BioRender.com.