Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi

Abstract

Mast cells are tissue-resident immune cells known best for their role in allergic reactions and inflammation. Upon activation, mast cells rapidly release histamine, lysosomal proteases and inflammatory mediators from large cytoplasmic granules via regulated exocytosis. This acute anaphylactic degranulation is followed by a late activation phase involving synthesis and secretion of cytokines, growth factors and other inflammatory mediators via the constitutive pathway that remains mechanistically ill-defined. Here we describe a role for an inflammation-induced endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in constitutive exocytosis in mast cells and macrophages. We show that IRAP endosomes are required for efficient secretion of the pro-inflammatory cytokines TNF-α and IL-6 in vitro and in vivo, but not for the regulatory cytokine IL-10. In line with this data, we find that IRAP-deficient mice are protected from TNF-dependent cisplatin-induced kidney injury and inflammatory arthritis. In the absence of IRAP, TNF fails to be efficiently exported from the Golgi. Subsequently, reduced co-localization of VAMP3+ endosomes with Stx4 was observed, while VAMP8-dependent exocytosis of secretory granules was facilitated. Chemical targeting of IRAP+ endosomes reduced cytokine secretion thereby highlighting this compartment as a promising target for the therapeutic control of inflammation.