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Absence of tumor necrosis factor supports alternative activation of macrophages in the liver after infection with Leishmania major

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Hu, S, Marshall, C, Darby, J, Wei, W, Lyons, AB ORCID: 0000-0002-8508-5853 and Korner, H ORCID: 0000-0003-4610-2814 2018 , 'Absence of tumor necrosis factor supports alternative activation of macrophages in the liver after infection with Leishmania major' , Frontiers in Immunology, vol. 9 , pp. 1-17 , doi: 10.3389/fimmu.2018.00001.

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Abstract

The absence of tumor necrosis factor (TNF) causes lethal infection by Leishmania major in normally resistant C57BL/6J (B6.WT) mice. The underlying pathogenic mechanism of this fatal disease has so far remained elusive. We found that B6.WT mice deficient for the tnf gene (B6.TNF-/-) displayed not only a non-healing cutaneous lesion but also a serious infection of the liver upon L. major inoculation. Infected B6.TNF-/- mice developed an enlarged liver that showed increased inflammation. Furthermore, we detected an accumulating monocyte-derived macrophage population (CD45+F4/80+CD11bhiLy6Clow) that displayed a M2 macrophage phenotype with high expression of CD206, arginase-1, and IL-6, supporting the notion that IL-6 could be involved in M2 differentiation. In in vitro experiments, we demonstrated that IL-6 upregulated M-CSF receptor expression and skewed monocyte differentiation from dendritic cells to macrophages. This was countered by the addition of TNF. Furthermore, TNF interfered with the activation of IL-6-induced gp130-signal transducer and activator of transcription (STAT) 3 and IL-4-STAT6 signaling, thereby abrogating IL-6-facilitated M2 macrophage polarization. Therefore, our results support the notion of a general role of TNF in the inflammatory activation of macrophages and define a new role of IL-6 signaling in macrophage polarization downstream of TNF.

Item Type: Article
Authors/Creators:Hu, S and Marshall, C and Darby, J and Wei, W and Lyons, AB and Korner, H
Keywords: Leishmania major, liver, tumor necrosis factor, monocytes, il-6
Journal or Publication Title: Frontiers in Immunology
Publisher: Frontiers Research Foundation
ISSN: 1664-3224
DOI / ID Number: 10.3389/fimmu.2018.00001
Copyright Information:

Copyright 2018 The AuthorsLicensed under Creative Commons Attribution 4.0 International (CC BY 4.0)https://creativecommons.org/licenses/by/4.0/

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