Bacillus anthracis Edema Toxin Inhibits Efferocytosis in Human Macrophages and Alters Efferocytic Receptor Signaling

Int J Mol Sci. 2019 Mar 7;20(5):1167. doi: 10.3390/ijms20051167.


The Bacillus anthracis Edema Toxin (ET), composed of a Protective Antigen (PA) and the Edema Factor (EF), is a cellular adenylate cyclase that alters host responses by elevating cyclic adenosine monophosphate (cAMP) to supraphysiologic levels. However, the role of ET in systemic anthrax is unclear. Efferocytosis is a cAMP-sensitive, anti-inflammatory process of apoptotic cell engulfment, the inhibition of which may promote sepsis in systemic anthrax. Here, we tested the hypothesis that ET inhibits efferocytosis by primary human macrophages and evaluated the mechanisms of altered efferocytic signaling. ET, but not PA or EF alone, inhibited the efferocytosis of early apoptotic neutrophils (PMN) by primary human M2 macrophages (polarized with IL-4, IL-10, and/or dexamethasone) at concentrations relevant to those encountered in systemic infection. ET inhibited Protein S- and MFGE8-dependent efferocytosis initiated by signaling through MerTK and αVβ5 receptors, respectively. ET inhibited Rac1 activation as well as the phosphorylation of Rac1 and key activating sites of calcium calmodulin-dependent kinases CamK1α, CamK4, and vasodilator-stimulated phosphoprotein, that were induced by the exposure of M2(Dex) macrophages to Protein S-opsonized apoptotic PMN. These results show that ET impairs macrophage efferocytosis and alters efferocytic receptor signaling.

Keywords: Bacillus anthracis; Edema Toxin; efferocytosis; macrophage.

MeSH terms

  • Antigens, Bacterial / pharmacology*
  • Antigens, Surface / metabolism
  • Bacillus anthracis / metabolism*
  • Bacterial Toxins / pharmacology*
  • Cell Polarity / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Cyclic AMP / metabolism
  • Dexamethasone / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Interleukin-10 / metabolism
  • Interleukin-4 / metabolism
  • Macrophages / cytology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Milk Proteins / metabolism
  • Neutrophils / cytology*
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Phagocytosis / drug effects*
  • Protein S / metabolism
  • Receptors, Vitronectin / metabolism
  • Signal Transduction / drug effects
  • c-Mer Tyrosine Kinase / metabolism


  • Antigens, Bacterial
  • Antigens, Surface
  • Bacterial Toxins
  • IL10 protein, human
  • IL4 protein, human
  • MFGE8 protein, human
  • Milk Proteins
  • Protein S
  • Receptors, Vitronectin
  • anthrax toxin
  • integrin alphaVbeta5
  • Interleukin-10
  • Interleukin-4
  • Dexamethasone
  • Cyclic AMP
  • MERTK protein, human
  • c-Mer Tyrosine Kinase