AUTHOR=Hu Shanshan , Marshall Cameron , Darby Jocelyn , Wei Wei , Lyons Alan Bruce , Körner Heinrich 

TITLE=Absence of Tumor Necrosis Factor Supports Alternative Activation of Macrophages in the Liver after Infection with Leishmania major

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00001

DOI=10.3389/fimmu.2018.00001

ISSN=1664-3224

ABSTRACT=<p>The absence of tumor necrosis factor (TNF) causes lethal infection by <italic>Leishmania major</italic> 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 <italic>tnf</italic> gene (B6.TNF<sup>−/−</sup>) displayed not only a non-healing cutaneous lesion but also a serious infection of the liver upon <italic>L. major</italic> inoculation. Infected B6.TNF<sup>−/−</sup> mice developed an enlarged liver that showed increased inflammation. Furthermore, we detected an accumulating monocyte-derived macrophage population (CD45<sup>+</sup>F4/80<sup>+</sup>CD11b<sup>hi</sup>Ly6C<sup>low</sup>) 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 <italic>in vitro</italic> 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.</p>