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Abstract

The absence of tumor necrosis factor (TNF) causes lethal infection by Leishmania major (L. major) in normally resistant mice C57BL/6J (B6.WT) mice, but the underlying mechanism has so far remained elusive. We found B6.WT mice without the TNF gene (B6.TNF-/-) displayed not only non-healing cutaneous lesions but also serious liver and spleen infection upon L. major infection. The enlarged liver showed increased inflammation and harbored a new monocyte- derived-macrophage population showing a CD45\(^+\)F4/80\(^+\)Ly6C\(^{low}\)CD11b\(^{hi}\) phenotype. This population continuously accumulated and typically displayed a M2 macrophage phenotype with high expression of CD206, Arginase-1 and interleukin-6 (IL-6). Of note, IL-6 is normally considered as a pro-inflammatory cytokine, but it also has been shown to have anti- inflammatory properties. Absence of TNF induced increased IL-6 expression and upregulated M-CSF receptor expression downstream. The elevated IL-6 level skewed monocyte differentiation from dendritic cells (DCs) to macrophages. Furthermore, TNF inhibited both IL-6-induced gp130-STAT3 and IL-4-STAT6 signaling activation, thereby abrogating an IL- 6 facilitated M2 macrophage polarization.
Spleens from B6.TNF-/- mice were around three times larger than B6.WT mice and contained significantly more parasites. Plasmacytoid dendritic cells (pDC) are the key immune inducing population during leishmaniasis, producing IL-12 and promoting a Th1 immune response. B6.TNF\(^{-/-}\) mice displayed significantly fewer pDC and a non-defined B220\(^+\) monocyte-derived cell population compared to B6.WT mice. T cells and B cells did not show significant differences between the two strains, but CD11b\(^+\)F4/80\(^+\) cells were found to be in higher numbers in B6.TNF\(^{-/-}\) mice.
Therefore, our results set the basis to investigate the role of IL-6 signaling in macrophage polarization. Our findings also demonstrated the critical role of TNF in the development of different DC populations, that may subsequently affect T cell-mediated protection against L. major infection. In conclusion, these findings may potentially explain the increased risk of opportunistic infection and relapses in patients receiving anti-TNF treatment.

Item Type:	Thesis - PhD
Authors/Creators:	Hu, S
Keywords:	Leishmania major, liver, spleen, tumor necrosis factor, monocytes, IL-6
Copyright Information:	Copyright 2017 the author
Additional Information:	Chapter 1 appears to be, in part, the equivalent of a post-print version of an article published as: Hu, S., Wei, W., Korner, H., 2017. The role of monocytes in models of infection by protozoan parasites. Molecular immunology, 88, 174-184 Chapters 3 and 4 appear to be, in part, the equivalent of a pre or post-print version of an article published as: Hu, S., Marshall, C., Darby, J., Wei, W., Lyons, A. B., Korner, H., 2018. Absence of tumor necrosis factor supports alternative activation of macrophages in the liver after infection with Leishmania major, Frontiers in immunology, 9:1. The article was licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/ © 2018 The Authors.
Related URLs:	Chapter 1 (published version) Chapters 3 and 4 (published version)
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