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


ABSTRACT: 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 FcγR-triggered arthritis, active systemic anaphylaxis and FcεRI-triggered passive systemic anaphylaxis were observed in IRAP-deficient versus wild-type mice. In mast cells FcεRI stimulation induced rapid plasma membrane recruitment of IRAP-positive endosomes. IRAP-deficient cells exhibited reduced secretory responses, calcium signaling and activating SykY519/520 phosphorylation albeit receptor tyrosine phosphorylation on β and γ subunits was not different. By contrast, in the absence of IRAP, SHP1-inactivating phosphorylation on Ser591 that controls Syk activity was decreased. Ex-vivo cell profiling after FcγR-triggered anaphylaxis confirmed decreased phosphorylation of both SykY519/520 and SHP-1S591 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.

SUBMITTER: Bratti M 

PROVIDER: S-EPMC9647545 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Bratti Manuela M   Vibhushan Shamila S   Longé Cyril C   Koumantou Despoina D   Ménasché Gaël G   Benhamou Marc M   Varin-Blank Nadine N   Blank Ulrich U   Saveanu Loredana L   Ben Mkaddem Sanae S  

Frontiers in immunology 20221027


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 FcγR-triggered arthritis, active systemic anaphylaxis and FcεRI-triggered passive systemic anaphylaxis were observed in IRAP-deficient <i>versus</i> wild-type mice. In mast cells FcεRI stimulation induced rapid plasma membrane r  ...[more]

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