Entamoeba histolytica‐Induced Caspase‐4/11 Activation Elicits a Pro‐Inflammatory Response in Macrophages

Abstract

Entamoeba histolytica (Eh) is a protozoan parasite that colonizes in/on the mucus layer and in 10% of individuals, Eh invades the colonic mucosa to cause amebic colitis. A hallmark of amebiasis is acute intestinal inflammation dominated by the secretion of pro‐inflammatory cytokines, interleukin (IL)‐1β and tumour necrosis factor (TNF)‐α. Eh in contact with macrophages activates caspase‐1 by the inflammasome complex resulting in the maturation of IL‐1β and ‐18. The role of inflammatory caspase‐4, ‐5, and ‐12 in humans are less understood. Caspase‐11, the murine homolog of caspase‐4, mediates non‐canonical inflammasome activation in response to particular pathogens, suggesting that caspase‐4 may have similar roles. As caspase‐4/11 might be an immune sensor in Eh infection the aim of this study was to identify a signature role for caspase‐4/11 in Eh‐induced macrophage responses. To determine if caspase‐4/11 was involved in inflammasome signalling, the gene was silenced with siRNA. Knockdown of caspase‐4/11 did not affect caspase‐1 activation or IL‐1β secretion in response to Eh. However, multiplex cytokine arrays showed marked up regulation of TNF‐α, MIP‐1β, and KC suggesting that caspase‐4/11 may have regulatory roles in the secretion of distinct cytokines/chemokines. Although there was no evidence for crosstalk between caspase‐4/11 and caspase‐1, these inflammatory caspases seem to play a critical role in regulating other cytokines/chemokines that shape the overall macrophage response towards Eh infection. Elucidating the role these inflammatory caspases play in Eh disease pathogenesis may shed light on new therapeutics to treat amebiasis.Grant Support: NSERC