Lysosomal solute carriers promote pro-inflammatory signaling and MHC-II antigen presentation in dendritic cells 2303674

Abstract

Abstract Introduction Mutations in lysosomal solute carrier transporters (SLCs) are associated with metabolic and inflammatory diseases. However, the molecular mechanisms that link nutrient sensing and transport with pro-inflammatory immune responses are unclear. Our data suggest that nutrient-dependent responses mediated by the lysosomal SLC15A4 and SLC29A3, which are associated with human inflammatory disorders, are required for optimal phagosomal signaling to the production of pro-inflammatory cytokines and MHC-II antigen (Ag) presentation in murine dendritic cells (DCs). Methods We have investigated the mechanisms of action of SLC15A4 and SLC29A3 in murine DCs by performing biochemical, flow cytometric and immunological assays, as well as live-cell imaging. We have analyzed cytokine secretion by ELISA, transcription factor nuclear translocation by subcellular fractionation and RNA seq, Ag presentation and T cell activation by flow cytometry and biochemical assays, and calcium measurements by live-cell imaging. Results We have found that the histidine transporter SLC15A4 promotes pro-inflammatory responses by activating the master regulator of cell fitness, mechanistic target of rapamycin complex 1 (mTORC1). SLC15A4 also promotes MHC-II Ag presentation after phagocytosis by mechanisms that likely depend on mTORC1. In contrast, the nucleoside transporter SLC29A3 promotes phagosomal signaling and MHC-II Ag presentation by maintaining nucleoside homeostasis and supporting phagosomal acidification and membrane dynamics, as well as the activation of the transcription factor (TF)EB. Conclusion Our findings suggest that SLC15A4 and SLC29A3 regulate phagosomal signaling in murine dendritic cells via differential mechanisms to promote anti-bacterial immunity while preventing excessive inflammation. Funding Source NIH R01 12582389 Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)