Hepatic amebiasis, predominantly occurring in men, is a focal destruction of the liver due to the invading protozoan Entamoeba histolytica. Classical monocytes as well as testosterone are identified to have important functions for the development of hepatic amebiasis in mice, but a link between testosterone and monocytes has not been identified. Here we show that testosterone treatment induces proinflammatory responses in human and mouse classical monocytes. When treated with 5α-dihydrotestosterone, a strong androgen receptor ligand, human classical monocytes increase CXCL1 production in the presence of Entamoeba histolytica antigens. Moreover, plasma testosterone levels of individuals undergoing transgender procedure correlate positively with the TNF and CXCL1 secretion from their cultured peripheral blood mononuclear cells following lipopolysaccharide stimulation. Finally, testosterone substitution of castrated male mice increases the frequency of TNF/CXCL1-producing classical monocytes during hepatic amebiasis, supporting the hypothesis that the effects of androgens may contribute to an increased risk of developing monocyte-mediated pathologies.

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With an estimated number of new cases annually of approximately 1.4 million, leishmaniasis belongs to the most important parasitic diseases in the world. Nevertheless, existing drugs against leishmaniasis in general have several drawbacks that urgently necessitate new drug development. A glycolipid molecule of the intestinal protozoan parasite Entamoeba histolytica and its synthetic analogs previously showed considerable immunotherapeutic effects against Leishmania major infection. Here, we designed and synthesized a series of new immunostimulatory compounds derived from the phosphatidylinositol b anchor of Entamoeba histolytica (EhPIb) subunit of the native compound and investigated their antileishmanial activity in vitro and in vivo in a murine model of cutaneous leishmaniasis. The new synthetic EhPIb analogs showed almost no toxicity in vitro. Treatment with the analogs significantly decreased the parasite load in murine and human macrophages in vitro. In addition, topical application of the EhPIb analog Eh-1 significantly reduced cutaneous lesions in the murine model, correlating with an increase in the production of selected Th1 cytokines. In addition, we could show in in vitro experiments that treatment with Eh-1 led to a decrease in mRNA expression of arginase-1 (Arg1) and interleukin 4 (IL-4), which are required by the parasites to circumvent their elimination by the immune response. The use of the host-targeting synthetic EhPIb compounds, either alone or in combination therapy with antiparasitic drugs, shows promise for treating cutaneous leishmaniasis and therefore might improve the current unsatisfactory status of chemotherapy against this infectious disease.

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Liver disorders due to infections are a substantial health concern in underdeveloped and industrialized countries. This includes not only hepatotropic viruses (e.g., hepatitis B, hepatitis C) but also bacterial and parasitic infections such as amebiasis, leishmaniasis, schistosomiasis, or echinococcosis. Recent studies of the immune mechanisms underlying liver disease show that monocytes play an essential role in determining patient outcomes. Monocytes are derived from the mononuclear phagocyte lineage in the bone marrow and are present in nearly all tissues of the body; these cells function as part of the early innate immune response that reacts to challenge by external pathogens. Due to their special ability to develop into tissue macrophages and dendritic cells and to change from an inflammatory to an anti-inflammatory phenotype, monocytes play a pivotal role in infectious and non-infectious liver diseases: they can maintain inflammation and support resolution of inflammation. Therefore, tight regulation of monocyte recruitment and termination of monocyte-driven immune responses in the liver is prerequisite to appropriate healing of organ damage. In this review, we discuss monocyte-dependent immune mechanisms underlying hepatic infectious disorders. Better understanding of these immune mechanisms may lead to development of new interventions to treat acute liver disease and prevent progression to organ failure.