Tetraspanins in the regulation of mast cell function

Abstract

Mast cells (MCs) are long-living immune cells highly specialized in the storage and release of different biologically active compounds and are involved in the regulation of innate and adaptive immunity. MC degranulation and replacement of MC granules are accompanied by active membrane remodelling. Tetraspanins represent an evolutionary conserved family of transmembrane proteins. By interacting with lipids and other membrane and intracellular proteins, they are involved in organisation of membrane protein complexes and act as "molecular facilitators" connecting extracellular and cytoplasmic signaling elements. MCs express different tetraspanins and MC degranulation is accompanied by changes in membrane organisation. Therefore, tetraspanins are very likely involved in the regulation of MC exocytosis and membrane reorganisation after degranulation. Antiviral response and production of exosomes are further aspects of MC function characterized by dynamic changes of membrane organization. In this review, we pay a particular attention to tetraspanin gene expression in different human and murine MC populations, discuss tetraspanin involvement in regulation of key MC signaling complexes, and analyze the potential contribution of tetraspanins to MC antiviral response and exosome production. In-depth knowledge of tetraspanin-mediated molecular mechanisms involved in different aspects of the regulation of MC response will be beneficial for patients with allergies, characterized by overwhelming MC reactions.

Keywords: Allergy; Antiviral immune response; Exosomes; FcεRI; Mast cell degranulation; Mast cells; Tetraspanins.

Fig. 1

Expression of tetraspanins in murine and human MCs. a Tetraspanin expression in different murine MC subsets. Gene expression was analyzed in following MC populations-tongue MCs (MC-To), esophagus MCs (MC-Es), trachea MCs (MC-Tr), peritoneal MCs (MC-PC), and skin MCs (MC-Sk) [45]. The heat map was generated with data from http://www.immgen.org/ choosing MCs as the cells of interest and using r gplot heatmap2. The gene expression level was determined by Affymetrix microarrays (GEO: GSE377448). Tetraspanins involved in the regulation of MC function are outlined. b Expression of tetraspanin genes in ex vivo human skin MCs isolated from three different donors. Expression data were generated by cap analysis of gene expression (CAGE) technology within the FANTOM5 project and published as Supplemental Table 3 in [61]. Plotting the extracted tetraspanin gene expression data was performed with r gplot heatmap2.  Tetraspanins identified by skin MC proteome analysis [62] are outlined

Fig. 2

Different tetraspanins in non-activated and activated MCs. Majority of tetraspanins is expressed on MCs surface with exception of CD63 that is expressed also on MCs preformed granules in non-activated MCs. MCs contain preformed granules and form multi-vesicular bodies that give rise to exosomes. Stimulation with IgE/Ag complexes leads to release of several mediators including histamine, proteases, cytokines, as well as exosomes and, probably, redistribution of tetraspanins. Whether MC tetraspanins are involved in regulation of c-kit, TLR, or GPCR-mediated signals is unknown. MCs’ exosomes contain several proteins, RNAs and DNAs and tetraspanins CD9, CD63, and CD81 were identified on their surface. Antibodies against several tetraspanins were found to inhibit degranulation (αCD63 and αCD81) or chemotaxis (αCD9). On the other hand, loss of CD63 leads to decreased degranulation and TNFα release, whereas loss of CD151 potentiates cytokine production