Abstract
Echinococcus multilocularis larvae, predominantly located in the liver, cause a tumor-like parasitic disease, alveolar echinococcosis (AE), that is characterized by increased infiltration of various immune cells, including macrophages, around the lesion that produces an “immunosuppressive” microenvironment, favoring its persistent infection. However, the role of hepatic macrophages in the host defense against E. multilocularis infection remains poorly defined. Using human liver tissues from patients with AE and a hepatic experimental mouse model of E. multilocularis, we investigated the phenotype and function of hepatic macrophages during the parasite infection. In the present study, we found that a large number of CD68+ macrophages accumulated around the metacestode lesion in the liver of human AE samples and that both S100A9+ proinflammatory (M1 phenotype) and CD163+ anti-inflammatory (M2 phenotype) macrophages were significantly higher in close liver tissue (CLT) than in distant liver tissue (DLT), whereas M2 macrophages represent the dominant macrophage population. Furthermore, E. multilocularis-infected mice exhibited a massive increase in macrophage (F4/80+) infiltration in the liver as early as day 5, and the infiltrated macrophages were mainly monocyte-derived macrophages (CD11bhi F4/80int MoMFs) that preferentially differentiated into the M1 phenotype (iNOS+) at the early stage of E. multilocularis infection and then polarized to anti-inflammatory macrophages of the M2 phenotype (CD206+) at the chronic stage of infection. We further showed that elimination of macrophages by treatment of mice with clodronate-liposomes before E. multilocularis infection impaired worm expulsion and was accompanied by a reduction in liver fibrosis, yielding a high parasite burden. These results suggest that hepatic macrophages may play a dual role in the establishment and development of E. multilocularis metacestodes in which early larvae clearance is promoted by M1 macrophages while persistent metacestode infection is favored by M2 macrophages.
Highlights
Alveolar echinococcosis (AE) is one of the most dangerous parasitic diseases distributed in the Northern Hemisphere and is caused by the larval stage of the tapeworm Echinococcus multilocularis (E. multilocularis) [1,2,3,4]
The increase in the number of CD163+ macrophages was larger than that of S100A9+ macrophages in the close liver tissue (CLT) specimens (9.4% of CD163+ vs. 5.2% of S100A9+), suggesting a predominantly anti-inflammatory response (Figures 1A, C–E). These findings suggest a role for infiltrating macrophages in human AE and provide a rationale for using animal models to further examine this phenomenon
Numerous studies on parasite or virus infection and tumor development in the liver have shown that hepatic macrophages are involved in the progression of liver inflammation and fibrosis, and they play a key role in controlling the pathogenesis of liver disease [38,39,40]
Summary
Alveolar echinococcosis (AE) is one of the most dangerous parasitic diseases distributed in the Northern Hemisphere and is caused by the larval stage of the tapeworm Echinococcus multilocularis (E. multilocularis) [1,2,3,4]. The intrahepatic localization and persistent proliferation of E. multilocularis usually elicit a severe hepatic granulomatous inflammation response characterized by attraction of various host immune cells around the metacestode lesion [12], which may produce an “immunosuppressive” microenvironment and might be of crucial importance in favoring persistent E. multilocularis infection. Similar to observations in human AE, macrophages were mainly located at the periphery of the lesion [14] These observations in humans and experimental studies in mice indicated that macrophages are among the main infiltrated cell population and may act as key immune regulators of the granulomatous inflammation response to maintain immune homoeostasis during persistent infection [15, 16]. The role of macrophages in the development of E. multilocularis larvae has not yet been fully elucidated
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