Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi.
Cytokine secretion
TNF
VAMP3
VAMP8
exocytic trafficking
inflammation
insulin-regulated aminopeptidase
mast cells
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
27
06
2022
revised:
31
12
2022
accepted:
11
01
2023
medline:
9
6
2023
pubmed:
29
1
2023
entrez:
28
1
2023
Statut:
ppublish
Résumé
On activation, mast cells rapidly release preformed inflammatory mediators from large cytoplasmic granules via regulated exocytosis. This acute degranulation is followed by a late activation phase involving synthesis and secretion of cytokines, growth factors, and other inflammatory molecules via the constitutive pathway that remains ill defined. We investigated the role for an insulin-responsive vesicle-like endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in the secretion of TNF-α and IL-6 in mast cells and macrophages. Murine knockout (KO) mouse models (IRAP-KO and kit-W IRAP-KO mice are protected from TNF-α-dependent kidney injury and inflammatory arthritis. In the absence of IRAP, TNF-α and IL-6 but not IL-10 fail to be efficiently secreted. Moreover, chemical targeting of IRAP endosomes reduced proinflammatory cytokine secretion. Mechanistically, impaired TNF-α export from the Golgi and reduced colocalization of vesicle-associated membrane protein (VAMP) 3-positive TNF-α transport vesicles with syntaxin 4 (aka Stx4) was observed in IRAP-KO mast cells, while VAMP8-dependent exocytosis of secretory granules was facilitated. IRAP plays a novel role in mast cell-mediated inflammation through the regulation of exocytic trafficking of cytokines.
Sections du résumé
BACKGROUND
On activation, mast cells rapidly release preformed inflammatory mediators from large cytoplasmic granules via regulated exocytosis. This acute degranulation is followed by a late activation phase involving synthesis and secretion of cytokines, growth factors, and other inflammatory molecules via the constitutive pathway that remains ill defined.
OBJECTIVE
We investigated the role for an insulin-responsive vesicle-like endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in the secretion of TNF-α and IL-6 in mast cells and macrophages.
METHODS
Murine knockout (KO) mouse models (IRAP-KO and kit-W
RESULTS
IRAP-KO mice are protected from TNF-α-dependent kidney injury and inflammatory arthritis. In the absence of IRAP, TNF-α and IL-6 but not IL-10 fail to be efficiently secreted. Moreover, chemical targeting of IRAP endosomes reduced proinflammatory cytokine secretion. Mechanistically, impaired TNF-α export from the Golgi and reduced colocalization of vesicle-associated membrane protein (VAMP) 3-positive TNF-α transport vesicles with syntaxin 4 (aka Stx4) was observed in IRAP-KO mast cells, while VAMP8-dependent exocytosis of secretory granules was facilitated.
CONCLUSION
IRAP plays a novel role in mast cell-mediated inflammation through the regulation of exocytic trafficking of cytokines.
Identifiants
pubmed: 36708814
pii: S0091-6749(23)00090-8
doi: 10.1016/j.jaci.2023.01.014
pii:
doi:
Substances chimiques
Aminopeptidases
EC 3.4.11.-
Cytokines
0
Insulin
0
Tumor Necrosis Factor-alpha
0
Interleukin-6
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1595-1608.e6Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.