Molecular Mechanisms of Mast Cell Activation by Cholesterol-Dependent Cytolysins

Abstract

Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of de novo synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.

Valproic acid restricts mast cell activation by Listeria monocytogenes

“…VPA decrease MC cytokine production by these TLR2 ligands, in similar way to what is observed in macrophages stimulated with Pam 22 . In addition, we observed that VPA inhibited MC activation with LLO, which activates MC in a TLR2-independent manner 14 , 30 through cholesterol dependent activation 36 mediated by ERK1/2 phosphorylation 49 . These observations indicate that VPA does not affect TLR2 expression in MC and suggest that this compound compromises L.m-mediated MC activation by modulating intracellular activation mechanisms involved in the MC response to this pathogen.…”

“…In fact, MC initiate the response against Listeria monocytogenes (L.m) by promoting the recruitment of neutrophils to the site of infection in an experimental model of murine listeriosis 9 . Moreover, L.m activates MC by triggering TLR2 and through cholesterol-dependent activation by listeriolysin O (LLO) 14 , 36 .…”

The regulatory role and mechanism of mast cells in tumor microenvironment

“…The classical activation pathway of MCs involves downstream signaling mediated by the high-affinity receptor (FceRI) for IgE on the MC surface. Additionally, MC membranes harbor various receptors activated by their ligands, including cytokine and chemokine receptors, Toll-like receptors (TLRs), and vascular endothelial growth factor receptors [11,12]. Moreover, studies have showed that MCs can selectively release particulate matter through a process known as segmental degranulation.…”

A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection

“…Moreover, studies of diverse infections have demonstrated that MCs can detect assault by bacterial cytolytic toxins 12 – 16 . Based on the latter studies, a common theme emerges, in which MCs respond vigorously to sublytic membrane perturbation that precedes toxin-mediated lysis 16 , 17 . It is unclear whether this mode of sensing also extends to other membrane-interfering events, such as the docking of bacterial secretion machineries to the plasma membrane.…”