Molecular Mechanisms of Mast Cell Activation by Cholesterol-Dependent Cytolysins

Front Immunol. 2021 Jun 23:12:670205. doi: 10.3389/fimmu.2021.670205. eCollection 2021.


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.

Keywords: Ca2+ signaling; cholesterol-dependent cytolysins; cytokine production; listeriolysin O; mast cell; pneumolysin; pore-forming toxins; streptolysin O.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Calcium Signaling
  • Cell Death
  • Cell Degranulation
  • Cell Membrane / immunology
  • Cell Membrane / metabolism*
  • Cell Membrane / microbiology
  • Cell Membrane / pathology
  • Cellular Microenvironment
  • Cholesterol / metabolism*
  • Cytokines / metabolism
  • Cytotoxins / metabolism*
  • Gram-Positive Bacteria / immunology
  • Gram-Positive Bacteria / metabolism*
  • Gram-Positive Bacterial Infections / immunology
  • Gram-Positive Bacterial Infections / metabolism*
  • Gram-Positive Bacterial Infections / microbiology
  • Gram-Positive Bacterial Infections / pathology
  • Host-Pathogen Interactions
  • Humans
  • Inflammation Mediators / metabolism
  • Mast Cells / immunology
  • Mast Cells / metabolism*
  • Mast Cells / microbiology
  • Mast Cells / pathology


  • Cytokines
  • Cytotoxins
  • Inflammation Mediators
  • Cholesterol