Mast cell mediators: their differential release and the secretory pathways involved - PubMed (original) (raw)

Review

Mast cell mediators: their differential release and the secretory pathways involved

Tae Chul Moon et al. Front Immunol. 2014.

Abstract

Mast cells (MC) are widely distributed throughout the body and are common at mucosal surfaces, a major host-environment interface. MC are functionally and phenotypically heterogeneous depending on the microenvironment in which they mature. Although MC have been classically viewed as effector cells of IgE-mediated allergic diseases, they are also recognized as important in host defense, innate and acquired immunity, homeostatic responses, and immunoregulation. MC activation can induce release of pre-formed mediators such as histamine from their granules, as well as release of de novo synthesized lipid mediators, cytokines, and chemokines that play diverse roles, not only in allergic reactions but also in numerous physiological and pathophysiological responses. Indeed, MC release their mediators in a discriminating and chronological manner, depending upon the stimuli involved and their signaling cascades (e.g., IgE-mediated or Toll-like receptor-mediated). However, the precise mechanisms underlying differential mediator release in response to these stimuli are poorly known. This review summarizes our knowledge of MC mediators and will focus on what is known about the discriminatory release of these mediators dependent upon diverse stimuli, MC phenotypes, and species of origin, as well as on the intracellular synthesis, storage, and secretory processes involved.

Keywords: exocytosis; exosome; granule; lipid body; lysosome; secretion.

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Figures

Figure 1

Figure 1

Mediator release from MC. MC release various mediators from different compartments following different stimuli. MC rapidly release pre-stored granule contents by piecemeal or anaphylactic degranulation. Immature progranules and mature granules can fuse with endosomes, and store lysosomal proteins. Some mediators can be released from granules and endosomes through exosomal secretion. Lipid mediators such as PGD2 and LTC4 are synthesized in lipid bodies, nuclear and ER membranes, and released through active transporters. De novo synthesized cytokines and chemokines packaged in secretory vesicles are released through constitutive exocytosis.

Figure 2

Figure 2

Model of genesis of MC secretory lysosomes (granules) and their heterogeneity/plasticity [adapted from Raposo et al. (43)]. Type I granules and type III granules are formed from lysosomal/endosomal pathway and by unit granule fusion from the trans-Golgi region, respectively. Secretory lysosomes that bud from trans-Golgi network contain MHC class II molecules, mannose-6-phosphate receptor (M6PR), and the lysosomal markers LAMP-1, -2, and β-hexosaminidase. It is postulated that post-endosomal, type II secretory lysosomes arise through the fusion of Type I and III granules. The relationship of this model to observations of heterogeneity of secretory lysosomes with regard to histamine or 5-HT content and VAMP-8 expression is unclear and there likely exists more granule heterogeneity/plasticity than three types (44). The mechanism of genesis of granule types is poorly understood (black area).

Figure 3

Figure 3

Model of lipid body biogenesis and structure. Neutral lipids synthesized in the ER accumulate between bilayer of ER membrane and bud off as a lipid body. Lipid bodies have phospholipid monolayer on their outside. However, lipid bodies contain a bilayer core structure inside, which provides a hydrophilic area. The bilayer core can be created by incorporation of multiple loops of ER membrane and explains how ER membrane proteins (e.g., caveolin-1 and ribosome) are incorporated into lipid bodies. However, the exact mechanism of formation of the bilayer structure is poorly understood. Enzymes required for eicosanoid production have been found in both outer membrane and core of lipid bodies. Increased intracellular Ca2+ after MC stimulation induces activation and translocation of cPLA2, 5-LO, and 15-LO to the lipid body membrane for eicosanoid synthesis. Further studies are required to unveil how MC control synthesis and secretion of arachidonic acid metabolites in a stimulus-specific fashion.

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