Immune complexes exposed on mast cell‐derived nanovesicles amplify allergic inflammation

Abstract

Ags. Studies are ongoing to compare nanovesicles derived from sera of atopic individuals before and during an acute phase of allergic reaction. Collectively, our data uncovered a new role for nanovesicles derived from activated MCs in the positive regulation of allergic responses, as depicted in our working model (Figure S6). Understanding how these nanovesicles influence the hypersensitivity reactions could help the development of more efficient therapies. ACK N OWLED G M ENTS This work was supported by the Italian Ministry of Education, Universities and Research-Dipartimenti di Eccellenza-L. 232/2016 and the Pasteur Institute-Cenci Bolognetti Foundation-Call 2012. EV is supported by a fellowship from AIRC (Associazione Italiana per la Ricerca sul Cancro). We are grateful to Dr J.-P. Kinet for generous access to anti-FcεRI β chain antibody and to Dr B. Wilson for helpful advices on exosome isolation. We thank Dr B. Zitti for isolating mouse bone marrow cells (mBMMCs), and Drs. G. Bernardini, F. Antonangeli, G. Sciumè and E. Sanseviero for technical advises on mBMMC culture. We also thank B. Milana for expert technical assistance, L. Simonelli for technical assistance in electron microscopy procedures and L. Cutini for IgE determination. The confocal fluorescence images were collected at the CLNS Imaging Facility of the Istituto Italiano di Tecnologia (Rome, Italy).

FcεRI Signaling in the Modulation of Allergic Response: Role of Mast Cell-Derived Exosomes

“…In this regard, we have previously reported in RBL-2H3 cells that upon antigen stimulation, FcεRIβ and γ subunits undergo ubiquitination, thus triggering receptor endocytosis from the cell surface to lysosomes for degradation [77,78] and envisaged a key role for the endocytic adapter Hrs [79]. More recently, we found that Hrs is required for exosome release by MCs, as well [51].…”

“…ESCRT complexes are composed of ESCRT-0 and ESCRT-I that promote cargo recruitment, while ESCRT-II and ESCRT-III, together with numerous accessory proteins, induce the inward budding of endosomal membrane and pinch off of ILVs. Notably, Hrs, a protein member of the ESCRT-0 complex, is critically involved in exosome biogenesis since its depletion on DCs, MCs, and HeLa cells strongly impairs nanovesicle secretion [51][52][53]. The ESCRT machinery also serves to ensure the proper composition of the vesicles.…”

“…Through both constitutive and induced exocytosis by means of IgE and multivalent antigens, mBMMCs and rodent MC lines release exosomes that shuttle several mRNA and microRNA and also deliver MHC II molecules and FcεRI subunits [13,51,57,[71][72][73].…”

“…* p < 0.05, ** p < 0.01, one-way ANOVA with Tukey's multiple comparison test. The technique used to isolate exosomes has been fully described in [51].…”

“…A recent report provides evidence that exosomes released from unstimulated mBMMCs contain FcεRI complexes able to bind to free IgE, thus decreasing circulating IgE levels and inhibiting allergic cascade [73]. However, there are several other lines of evidence that support a positive immune regulatory role for MC-derived exosomes [51,[80][81][82]. The interaction of exosomes produced by unstimulated mBMMCs with naïve T cells results in their polarization towards the Th2 phenotype in vitro [82].…”