The phagosomal solute transporter SLC15A4 promotes inflammasome activity via mTORC1 signaling and autophagy restraint in dendritic cells

Abstract

Phagocytosis is the necessary first step to sense foreign microbes or particles and enables activation of innate immune pathways such as inflammasomes. However, the molecular mechanisms underlying how phagosomes modulate inflammasome activity are not fully understood. We show that in murine dendritic cells (DCs), the lysosomal histidine/peptide solute carrier transporter SLC15A4, associated with human inflammatory disorders, is recruited to phagosomes and is required for optimal inflammasome activity after infectious or sterile stimuli. Dextran sodium sulfate‐treated SLC15A4‐deficient mice exhibit decreased colon inflammation, reduced IL‐1β production by intestinal DCs, and increased autophagy. Similarly, SLC15A4‐deficient DCs infected with Salmonella typhimurium show reduced caspase‐1 cleavage and IL‐1β production. This correlates with peripheral NLRC4 inflammasome assembly and increased autophagy. Overexpression of constitutively active mTORC1 rescues decreased IL‐1β levels and caspase1 cleavage, and restores perinuclear inflammasome positioning. Our findings support that SLC15A4 couples phagocytosis with inflammasome perinuclear assembly and inhibition of autophagy through phagosomal content sensing. Our data also reveal the previously unappreciated importance of mTORC1 signaling pathways to promote and sustain inflammasome activity. image The molecular mechanisms connecting phagocytosis, inflammasome activity, and autophagy are not entirely elucidated. Here, we identify the phagosomal solute carrier transporter SLC15A4 as a novel positive regulator of inflammasome activity by modulating mTORC1 function: SLC15A4‐deficient mice show decreased inflammation and increased autophagy in a dextran sodium sulfate‐induced mouse model of colitis. SLC15A4 is recruited to phagosomes and promotes mTORC1 activity upon inflammasome stimulation in bone marrow‐derived dendritic cells (BMDCs). mTORC1 signaling promotes the positioning of NLRC4 inflammasomes in the perinuclear region and prevents autophagy induction. Decreased inflammasome activity in SLC15A4‐deficient BMDCs is restored by expression of constitutively active mTORC1 or knock‐down of autophagy proteins ATG5 or ATG7.