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 the inventors 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. Chemical targeting of IRAP+ endosomes reduced pro-inflammatory cytokine secretion thereby highlighting this compartment as a promising target for the therapeutic control of inflammation.

Abstract: A 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof, in particular masitinib or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of sickle cell disease in a patient in need thereof. Also, a 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof, in particular masitinib or a pharmaceutically acceptable salt or solvate thereof, for use in the prevention and/or treatment of acute chest syndrome (ACS) in a sickle cell disease patient in need thereof.