Background: Upon 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: Here we investigate the role for an insulin-responsive vesicle (IRV)-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 ko mouse models (IRAPko and kit-Wsh/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: We show that IRAPko 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 pro-inflammatory cytokine secretion. Mechanistically, impaired TNF-α export from the Golgi and reduced co-localization of VAMP3+ TNF-α transport vesicles with Stx4 was observed in IRAPko mast cells, while VAMP8-dependent exocytosis of secretory granules was facilitated. Conclusion: Our study describes a novel role for IRAP in mast cell-mediated inflammation through the regulation of exocytic trafficking of cytokines.