Insulin-regulated aminopeptidase contributes to setting the intensity of FcR-mediated inflammation

The function of intracellular trafficking in immune-complex triggered inflammation remains poorly understood. Here, we investigated the role of Insulin-Regulated Amino Peptidase (IRAP)-positive endosomal compartments in Fc receptor (FcR)-induced inflammation. Less severe Fc gamma R-triggered arthritis, active systemic anaphylaxis and Fc epsilon RI-triggered passive systemic anaphylaxis were observed in IRAP-deficient versus wild-type mice. In mast cells Fc epsilon RI stimulation induced rapid plasma membrane recruitment of IRAP-positive endosomes. IRAP-deficient cells exhibited reduced secretory responses, calcium signaling and activating Syk(Y519/520) phosphorylation albeit receptor tyrosine phosphorylation on beta and gamma subunits was not different. By contrast, in the absence of IRAP, SHP1-inactivating phosphorylation on Ser(591) that controls Syk activity was decreased. Ex-vivo cell profiling after Fc gamma R-triggered anaphylaxis confirmed decreased phosphorylation of both Syk(Y519/520) and SHP-1(S591) in IRAP-deficient neutrophils and monocytes. Thus, IRAP-positive endosomal compartments, in promoting inhibition of SHP-1 during FcR signaling, control the extent of phosphorylation events at the plasma membrane and contribute to setting the intensity of immune-complex triggered inflammatory diseases.

Automated summary

The study found that IRAP-positive endosomal compartments play a significant role in promoting inhibition of SHP-1 and controlling the extent of phosphorylation events at the plasma membrane, thus impacting the severity of immune-complex triggered inflammatory diseases.