IL-23 prevents IL-13-dependent tissue repair associated with Ly6C^lo monocytes in Entamoeba histolytica-induced liver damage

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• 作者：Jill Noll¹ ; ^&dagger ; ; Elena Helk¹ ; ^&dagger ; ; Helena Fehling¹ ; Hannah Bernin¹ ; Claudia Marggraff¹ ; Thomas Jacobs¹ ; Samuel Huber² ; Penelope Pelczar² ; Thomas Ernst³ ; Harald Ittrich³ ; Benjamin Otto⁴ ; Hans-Willi Mittrü ; cker⁵ ; Christoph Hö ; lscher⁶ ; Frank Tacke⁷ ; Iris Bruchhaus¹ ; Egbert Tannich¹ ; Hannelore Lotter¹ ; ^{lotter@bnitm.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：IL ; interleukin ; CCR2 ; C-C chemokine receptor 2 ; mAb ; monoclonal antibody ; E. histolytica ; Entamoeba histolytica ; ALA ; amebic liver abscess ; TNF ; tumor necrosis factor ; Th ; T helper ; CCL2 ; C-C chemokine ligand 2 ; Ly6C ; lymphocyte antigen 6C ; NOS2 ; nitric oxide synthase 2 ; Arg1 ; arginase 1 ; IFN ; interferon ; CD ; cluster of differentiation ; IL-23R ; IL-23 receptor ; TLR ; toll like receptor ; MRI ; magnet resonance imaging ; Nr4a1 ; Nuclear Receptor Subfamily 4 ; Group A ; Member 1 ; MFI ; mean fluorescence i
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：64
• 期：5
• 页码：1147-1157
• 全文大小：2585 K

文摘

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.