SLC15A4 favors inflammasome function via mTORC1 signaling and autophagy restraint in dendritic cells

Abstract

Phagocytosis is the first step in the assessment of foreign microbes or particles and enables activation of innate immune pathways such as the inflammasome. However, missing links between phagosomes and inflammasomes remain to be discovered. 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 sulphate-treated SLC15A4-deficient mice exhibit decreased colon inflammation, reduced IL-1{beta} production by intestinal DCs and increased autophagy. Similarly, SLC15A4-deficient DCs infected with Salmonella typhimurium show reduced caspase-1 cleavage and IL-1{beta} production. This correlates with peripheral NLRC4 inflammasome assembly and increased autophagy. Overexpression of constitutively active mTORC1 rescues decreased IL-1{beta} levels and caspase-1 cleavage, and restores perinuclear inflammasome positioning. Our findings suggest that SLC15A4 is a novel link that 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.