A review of the proposed role of neutrophils in rodent amebic liver abscess models

Abstract

Host invasion by Entamoeba histolytica, the pathogenic agent of amebiasis, can lead to the development of amebic liver abscess (ALA). Due to the difficulty of exploring host and amebic factors involved in the pathogenesis of ALA in humans, most studies have been conducted with animal models (e.g., mice, gerbils, and hamsters). Histopathological findings reveal that the chronic phase of ALA in humans corresponds to lytic or liquefactive necrosis, whereas in rodent models there is granulomatous inflammation. However, the use of animal models has provided important information on molecules and mechanisms of the host/parasite interaction. Hence, the present review discusses the possible role of neutrophils in the effector immune response in ALA in rodents. Properly activated neutrophils are probably successful in eliminating amebas through oxidative and non-oxidative mechanisms, including neutrophil degranulation, the generation of free radicals (O2(-), H2O2, HOCl) and peroxynitrite, the activation of NADPH-oxidase and myeloperoxidase (MPO) enzymes, and the formation of neutrophil extracellular traps (NETs). On the other hand, if amebas are not eliminated in the early stages of infection, they trigger a prolonged and exaggerated inflammatory response that apparently causes ALAs. Genetic differences in animals and humans are likely to be key to a successful host immune response.

Figure 1.

The initial contact between the lectin and neutrophil receptors promotes CR3 expression by neutrophils, and then the interaction of this molecule with iC3b induces neutrophil degranulation. It is likely that neutrophils are activated due to the recognition by TLR-2 and TLR-4 of lipopeptidophosphoglycan (LPPG) from E. histolytica. Activated neutrophils undergo an “oxidative burst” that results in an increased production of superoxide (O₂⁻) by the NADPH-oxidase system. Superoxide dismutase (SOD) rapidly converts O₂⁻ to hydrogen peroxide (H₂O₂, a highly oxidizing agent), and to the substrate of MPO for the formation of hypochlorous acid (HOCl). During this oxidative burst, neutrophils express high levels of iNOS, causing an increase in •NO. Another powerful oxidant is peroxynitrite, formed by the reaction of •NO and O₂•−.

Figure 2.

Activated neutrophils provide signals for the activation and maturation of macrophages, which in turn release IL-1β, TNF-α, G-CSF, and GM-CSF. These cytokines extend the life span of neutrophils at sites of inflammation. The interaction of lipopeptidophosphoglycan (LPPG) with TLR-2 and TLR-4 results in the activation of NF-kappa B and the release of IL-8, IL-10, IL-12p40, and TNF-α from human macrophages. Activated neutrophils enhance the production of reactive oxygen species (ROS), activating NF-kB and increasing neutrophil degranulation. Primary granules contain MPO, defensins, lysozyme, bactericidal/permeability-increasing protein (BPI), neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CG). Secondary granules are characterized by the presence of lactoferrin, neutrophil gelatinase-associated lipocalin (NGAL), human cationic antimicrobial protein 18 or cathelin (hCAP-18), and lysozyme. MPO can bind to monocytes, which might lead to the production of ROS and proinflammatory cytokines. Another function of neutrophils is the formation of neutrophil extracellular traps (NETs), composed of DNA bound with antimicrobial components (e.g., bacterial permeability-increasing protein, myeloperoxidase, elastase, lactoferrin). NET formation may have an important role in combating amebas.