RESUMO
BACKGROUND & AIMS: The IL-23/IL-17 axis plays an important role in the pathogenesis of autoimmune diseases and the pathological consequences of infection. We previously showed that immunopathologic mechanisms mediated by inflammatory monocytes underlie the severe focal liver damage induced by the protozoan parasite, Entamoeba histolytica. Here, we analyze the contribution of the IL-23/IL-17 axis to the induction and subsequent recovery from parasite-induced liver damage. METHODS: IL-23p19(-/-), IL-17A/F(-/-), CCR2(-/-), and wild-type (WT) mice were intra-hepatically infected with E. histolytica trophozoites and disease onset and recovery were analyzed by magnetic resonance imaging. Liver-specific gene and protein expression during infection was examined by qPCR, microarray, FACS analysis and immunohistochemistry. Immuno-depletion and substitution experiments were performed in IL-23p19(-/-) and WT mice to investigate the role of IL-13 in disease outcome. RESULTS: Liver damage in infected IL-23p19(-/-), IL-17A/F(-/-), and CCR2(-/-) mice was strongly attenuated compared with that in WT mice. IL-23p19(-/-) mice showed reduced accumulation of IL-17 and CCL2 mRNA and proteins. Increased numbers of IL-13-producing CD11b(+)Ly6C(lo) monocytes were associated with disease attenuation in IL-23p19(-/-) mice. Immuno-depletion of IL-13 in IL-23p19(-/-) mice reversed this attenuation and treatment of infected WT mice with an IL-13/anti-IL-13-mAb complex supported liver recovery. CONCLUSIONS: The IL-23/IL-17 axis plays a critical role in the immunopathology of hepatic amebiasis. IL-13 secreted by CD11b(+)Ly6C(lo) monocytes may be associated with recovery from liver damage. An IL-13/anti-IL13-mAb complex mimics this function, suggesting a novel therapeutic option to support tissue healing after liver damage.
Assuntos
Antígenos Ly/imunologia , Entamoeba histolytica/isolamento & purificação , Regulação da Expressão Gênica , Interleucina-13/genética , Interleucina-23/genética , Hepatopatias Parasitárias/genética , Monócitos/patologia , Animais , DNA/genética , Modelos Animais de Doenças , Entamebíase/genética , Entamebíase/metabolismo , Entamebíase/patologia , Interleucina-13/biossíntese , Interleucina-23/biossíntese , Hepatopatias Parasitárias/metabolismo , Hepatopatias Parasitárias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Reação em Cadeia da PolimeraseRESUMO
Amebic liver abscess (ALA), a parasitic disease due to infection with the protozoan Entamoeba histolytica, occurs age and gender dependent with strong preferences for adult males. Using a mouse model for ALA with a similar male bias for the disease, we have investigated the role of female and male sexual hormones and provide evidence for a strong contribution of testosterone. Removal of testosterone by orchiectomy significantly reduced sizes of abscesses in male mice, while substitution of testosterone increased development of ALA in female mice. Activation of natural killer T (NKT) cells, which are known to be important for the control of ALA, is influenced by testosterone. Specifically activated NKT cells isolated from female mice produce more IFNγ compared to NKT cells derived from male mice. This high level production of IFNγ in female derived NKT cells was inhibited by testosterone substitution, while the IFNγ production in male derived NKT cells was increased by orchiectomy. Gender dependent differences were not a result of differences in the total number of NKT cells, but a result of a higher activation potential for the CD4(-) NKT cell subpopulation in female mice. Taken together, we conclude that the hormone status of the host, in particular the testosterone level, determines susceptibility to ALA at least in a mouse model of the disease.
Assuntos
Entamoeba histolytica/fisiologia , Interferon gama/metabolismo , Abscesso Hepático Amebiano/imunologia , Abscesso Hepático Amebiano/metabolismo , Células T Matadoras Naturais/metabolismo , Testosterona/metabolismo , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/parasitologia , Suscetibilidade a Doenças , Entamoeba histolytica/química , Feminino , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/parasitologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Caracteres Sexuais , Testosterona/sangueRESUMO
Amebic liver abscess (ALA) is a focal destruction of liver tissue due to infection by the protozoan parasite Entamoeba histolytica (E. histolytica). Host tissue damage is attributed mainly to parasite pathogenicity factors, but massive early accumulation of mononuclear cells, including neutrophils, inflammatory monocytes and macrophages, at the site of infection raises the question of whether these cells also contribute to tissue damage. Using highly selective depletion strategies and cell-specific knockout mice, the relative contribution of innate immune cell populations to liver destruction during amebic infection was investigated. Neutrophils were not required for amebic infection nor did they appear to be substantially involved in tissue damage. In contrast, Kupffer cells and inflammatory monocytes contributed substantially to liver destruction during ALA, and tissue damage was mediated primarily by TNFα. These data indicate that besides direct antiparasitic drugs, modulating innate immune responses may potentially be beneficial in limiting ALA pathogenesis.