Abstract
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.
Highlights
Humans acquire anthrax by exposure to Bacillus anthracis spores through cutaneous, gastrointestinal, inhalational, or blood-borne routes
Efferocytosis has been reported to be inhibited by elevated cellular cyclic adenosine monophosphate (cAMP) [12] and requires the binding of macrophages to apoptotic cells followed by macrophage signaling events that lead to Rac1-dependent apoptotic cell engulfment [13,14,15]
The results demonstrate that Edema Toxin (ET) inhibits macrophage-mediated efferocytosis, Rac1 signaling, and the phosphorylation of Ca2+/calmodulin-dependent protein kinases, Rac1 and vasodilator-stimulated phosphoprotein (VASP) induced by apoptotic cell exposure
Summary
Humans acquire anthrax by exposure to Bacillus anthracis spores through cutaneous, gastrointestinal, inhalational, or blood-borne routes. There are approximately 12 known signaling receptors that can be divided into (i) those that require bridge proteins to bind apoptotic cells and (ii) those that do not [13]. Efferocytic macrophages in secondary lymphoid organs express MerTK [10] and alternative/M2-like markers CD163 and CD206 [20] Glucocorticoids such as dexamethasone (Dex), which have been historically used to treat severe sepsis [21,22], enhance macrophage efferocytosis by increasing the expression of the efferocytosis receptor MerTK and its cofactors Protein S and Gas6 [23,24]. The results demonstrate that ET inhibits macrophage-mediated efferocytosis, Rac signaling, and the phosphorylation of Ca2+/calmodulin-dependent protein kinases, Rac and vasodilator-stimulated phosphoprotein (VASP) induced by apoptotic cell exposure
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