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Cystic echinococcosis (CE) is a worldwide neglected zoonotic disease caused by infection with the larval stage of the tapeworm Echinococcus granulosus sensu lato (E. granulosus s.l.), which predominantly resides in the liver accompanied by mild inflammation. Macrophages constitute the main cellular component of the liver and play a central role in controlling the progression of inflammation and liver fibrosis. However, the role of hepatic macrophages in the establishment and growth of hydatid cysts in the liver during E. granulosus sensu stricto (E. granulosus s.s.) infection has not been fully elucidated. Here, we showed that CD68+ macrophages accumulated in pericystic areas of the liver and that the expression of CD163, a marker of anti-inflammatory macrophages, was more evident in active CE patients than in inactive CE patients. Moreover, in a mouse model of E. granulosus s.s. infection, the pool of hepatic macrophages expanded dramatically through the attraction of massive amounts of monocyte-derived macrophages (MoMFs) to the infection site. These infiltrating macrophages preferentially polarized toward an iNOS+ proinflammatory phenotype at the early stage and then toward a CD206+ anti-inflammatory phenotype at the late stage. Notably, the resident Kupffer cells (KCs) predominantly maintained an anti-inflammatory phenotype to favor persistent E. granulosus s.s. infection. In addition, depletion of hepatic macrophages promoted E. granulosus s.s. larval establishment and growth partially by inhibiting CD4+ T-cell recruitment and liver fibrosis. The above findings demonstrated that hepatic macrophages play a vital role in the progression of CE, contributing to a better understanding of the local inflammatory responses surrounding hydatid cysts and possibly facilitating the design of novel therapeutic approaches for CE. Author summary: Cystic echinococcosis (CE) is one of the neglected zoonoses caused by Echinococcus granulosus s.l. larvae and is a worldwide public health problem. Previous study showed that CE is usually characterized by mild local inflammation, indicating that E. granulosus s.l. can control liver inflammation to shape an 'immunosuppressive' microenvironment, a balance between pro- and anti-inflammatory responses to maintain immune homoeostasis during persistent infection. Here, by combining data from human CE samples and animal models, we found that hepatic macrophages are involved in the control of liver inflammation to favor persistent E. granulosus s.s. infection. The pool of hepatic macrophages expanded dramatically at the early stage through the attraction of massive amounts of MoMFs that preferentially initially polarized toward a proinflammatory phenotype and then toward an anti-inflammatory phenotype to favor persistent infection at the late stage after infection. Depletion of hepatic macrophages accelerated hydatid cyst establishment and growth by inhibiting CD4+ T-cell infiltration and liver fibrosis during E. granulosus s.s. infection. Our findings contribute to a better understanding of the local microenvironment in CE and possibly facilitate the design of novel therapeutic approaches for CE that target hepatic macrophages. [ABSTRACT FROM AUTHOR]

Infection with the cestode Echinococcus multilocularis (E. multilocularis) causes alveolar echinococcosis (AE), a tumor-like disease predominantly affecting the liver but able to spread to any organ. T cells develop functional defects during chronic E. multilocularis infection, mostly due to upregulation of inhibitory receptors such as T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and programmed death-1 (PD-1). However, the role of lymphocyte activation gene-3 (LAG3), an inhibitory receptor, in AE infection remains to be determined. Here, we discovered that high expression of LAG3 was mainly found in CD4+ T cells and induced regulatory T cells (iTregs) in close liver tissue (CLT) from AE patients. In a mouse model of E. multilocularis infection, LAG3 expression was predominantly found in T helper 2 (Th2) and Treg subsets, which secreted significantly more IL-4 and IL-10, resulting in host immune tolerance and disease progression at a late stage. Furthermore, LAG3 deficiency was found to drive the development of effector memory CD4+ T cells and enhance the type 1 CD4+ T-cell immune response, thus inhibiting metacestode growth in vivo. In addition, CD4+ T cells from LAG3-deficient mice produced more IFN-γ and less IL-4 when stimulated by E. multilocularis protoscoleces (EmP) antigen in vitro. Finally, adoptive transfer experiments showed that LAG3-knockout (KO) CD4+ T cells were more likely to develop into Th1 cells and less likely to develop into Tregs in recipient mice. Our work reveals that high expression of LAG3 accelerates AE disease progression by modulating the immune imbalance of CD4+ T-cell subsets. These findings may provide a novel immunotherapeutic strategy against E. multilocularis infection. Author summary: Alveolar echinococcosis (AE) is a parasitic disease with high mortality caused by E. multilocularis infection. Our previous studies confirmed that T-cell-mediated cellular immunity, especially that mediated by CD4+ T cells, plays a key role in limiting metacestode growth. Here, we report that high LAG3 expression in liver-infiltrating CD4+ T cells is associated with their immune imbalance in AE patients and a mouse model of later-stage disease. High expression of LAG3 promotes the formation of Th2 cells and Tregs, and LAG3 deficiency induces a shift in the immune response to the Th1 type to delay the growth of metacestodes in chronic E. multilocularis infection. These findings suggest that LAG3 blockade may be an effective immune strategy for the treatment of AE patients. [ABSTRACT FROM AUTHOR]