Role of K+ Channels in Alveolar Macrophages-Mediated Inflammatory Response upon Anthrax Lethal Toxin Stimulation

Abstract

The causes of rapid death in anthrax infection both in animals and humans are unknown and concern over the use for biological warfare has renewed interest in elucidating the mechanisms of anthrax induced inflammation. Interleukin-1β (IL-1β) secretion is an important inflammatory response against anthrax lethal toxin (LeTx) a virulence factor of Bacillus anthracis. Here, we report that LeTx induces a significant increase in inwardly-rectifying K+ (Kir) and voltage-gated K+ (Kv) currents in mouse and human macrophages. Furthermore, we also show that blocking either Kir or Kv channels significantly inhibits LeTx-induced IL-1β secretion suggesting that activation of macrophage K+ channels plays an important role in LeTx-induced inflammatory response. In addition, we also investigated the role of macrophage K+ channels in macrophage priming, a well-known macrophage infection model involving pre-exposure of the cells to a low level of antigen that augments the response to subsequent challenge. Specifically, priming of alveolar macrophages by either Lipopolysaccharides (LPS), an endotoxin of all gram-negative bacteria, or Bacillus spores, augments inflammatory response upon LeTx stimulation as compared to unprimed cells challenged with LeTx alone. Our study shows that pre-exposure to low levels of LPS or to the spores also significantly augments LeTx-induced activation of macrophage K+ channels suggesting that activation of K+ channels might be part of the priming mechanism.