SLC15A4 is a proton-coupled amino acid/oligopeptide transporter that resides in the late endosome/lysosome of immune cells. We have reported that SLC15A4 is necessary for endo/lysosome-dependent inflammatory responses of DCs and B cells including TLR7/9- or mTORC1-mediated type I IFN signaling by controlling amino acids/proton concentration in the vesicles.
We also investigated the role of SLC15A4 in the lysosome-dependent functions of mast cells that have specialized lysosomes where histamine, proteases and other inflammatory mediators are stored to secrete upon allergen challenges.
SLC15A4-/- mast cells showed striking alteration of lysosomal morphology. This phenotype was caused by enhancement of lysosome biogenesis, since nuclear localization of TFEB, a master regulator of lysosome biogenesis, which is regulated by mTORC1, was augmented in SLC15A4-deficient mast cells. Upon FcεRI crosslinking, SLC15A4-/- mast cells released higher amounts of histamine than wild type (WT). Consistent with this, serum histamine levels were increased in SLC15A4-deficient mice in IgE-mediated passive anaphylaxis. In contrast, FcεRI-mediated cytokine productions such as TNFα or IL-6 in SLC15A4-/- mice were comparable with WT mice. When mast cells were stimulated with IL-33, SLC15A4-/- mast cells produced higher amounts of inflammatory cytokines than WT. Furthermore, SLC15A4-deficient mice showed enhanced response than WT in airway inflammation induced by IL-33. Our results indicated that SLC15A4-mediated regulation of endo/lysosomal condition have an enormous impact on mast cell’s effector functions and subsequent allergic responses.