| First Author | Weimershaus M | Year | 2023 |
| Journal | J Allergy Clin Immunol | PubMed ID | 36708814 |
| Mgi Jnum | J:334494 | Mgi Id | MGI:7441747 |
| Doi | 10.1016/j.jaci.2023.01.014 | Citation | Weimershaus M, et al. (2023) Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi. J Allergy Clin Immunol |
| abstractText | 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-alpha and IL-6 in mast cells and macrophages. METHODS: Murine knockout (KO) mouse models (IRAP-KO and kit-W(sh/sh)) were used to study inflammatory disease models and to measure and mechanistically investigate cytokine secretion and degranulation in bone marrow-derived mast cells in vitro. RESULTS: IRAP-KO mice are protected from TNF-alpha-dependent kidney injury and inflammatory arthritis. In the absence of IRAP, TNF-alpha 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-alpha export from the Golgi and reduced colocalization of vesicle-associated membrane protein (VAMP) 3-positive TNF-alpha 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. |
