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

Weimershaus, M.; Carvalho, C.; Enee, E.; Rignault, R.; Dussiot, M.; van Endert, P.; Maciel, T. T.; Hermine, O.

doi:10.1101/2022.01.21.477149

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bioRxiv · 10.1101/2022.01.21.477149

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

Weimershaus, M.·Carvalho, C.·Enee, E.·Rignault, R.·Dussiot, M.·van Endert, P.·Maciel, T. T.·Hermine, O.

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Abstract

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. Here we describe a role for an insulin-responsive vesicle-like endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in the secretion of TNF-- and IL-6 in mast cells and macrophages. IRAP-deficient mice are protected from TNF--dependent 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 pro-inflammatory cytokine secretion thereby highlighting this compartment as a promising target for the therapeutic control of inflammation.

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Weimershaus, M., Carvalho, C., Enee, E., Rignault, R., Dussiot, M., van Endert, P., Maciel, T. T., Hermine, O.. 2022-01-22. Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi. https://doi.org/10.1101/2022.01.21.477149

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