Inflammasome responses to Legionella pneumophila in human macrophages (INM6P.414)

Inflammasome activation is important for defense against intracellular pathogens because it induces cell death and regulates the secretion of IL-1 family cytokines. The canonical inflammasome activates caspase-1 to mediate cell death and cytokine release. In murine cells, caspase-11 also contributes to inflammasome activation. For Legionella pneumophila and other Gram-negative bacteria, caspase-11 controls IL-1α release and cell death and contributes to IL-1β and IL-18 secretion. However, humans do not encode caspase-11. Instead, humans encode caspase-4 and caspase-5, two closely related homologs of caspase-11. Therefore, we aim to determine the inflammasome components in human cells that respond to intracellular pathogens, using L. pneumophila , the causative agent of the severe pneumonia known as Legionnaires’ disease in humans, as a model. We find that both immortalized human monocytes and primary human monocyte-derived macrophages activate the inflammasome in a manner dependent on the type IV secretion system, a virulence factor the bacterium uses to establish its intracellular niche. While IL-1β secretion requires caspase-1 catalytic activity, IL-1α release and cell death are independent of caspase-1 activity, implicating caspase-4 or -5 in the response to pathogenic L. pneumophila . Our findings demonstrate that human caspase-4 and/or -5 may function similarly to mouse caspase-11 to facilitate inflammasome activation in human macrophages.