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

Front Immunol. 2018 Jan 19;9:1. doi: 10.3389/fimmu.2018.00001. eCollection 2018.

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.

Keywords: IL-6; Leishmania major; liver; monocytes; tumor necrosis factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / biosynthesis
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Cytokine Receptor gp130 / metabolism
  • Inflammation / immunology
  • Interleukin-4 / metabolism
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / immunology*
  • Lectins, C-Type / biosynthesis
  • Leishmania major / immunology
  • Leishmaniasis, Cutaneous / immunology
  • Leishmaniasis, Cutaneous / parasitology
  • Liver / immunology*
  • Liver / parasitology
  • Liver / pathology
  • Macrophage Activation / genetics
  • Macrophage Activation / immunology*
  • Macrophages / cytology
  • Macrophages / immunology*
  • Mannose-Binding Lectins / biosynthesis
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / cytology
  • Parasite Load
  • Receptor, Macrophage Colony-Stimulating Factor / biosynthesis
  • Receptors, Cell Surface / biosynthesis
  • STAT3 Transcription Factor / metabolism
  • STAT6 Transcription Factor / metabolism
  • Tumor Necrosis Factor-alpha / genetics*

Substances

  • Interleukin-6
  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Receptors, Cell Surface
  • STAT3 Transcription Factor
  • STAT6 Transcription Factor
  • Stat3 protein, mouse
  • Stat6 protein, mouse
  • Tumor Necrosis Factor-alpha
  • interleukin-6, mouse
  • mannose receptor
  • Cytokine Receptor gp130
  • Interleukin-4
  • Receptor, Macrophage Colony-Stimulating Factor
  • Arginase