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Published on: August 2, 2021
Ly6C- Monocytes Regulate Parasite-Induced Liver Inflammation by Inducing the Differentiation of Pathogenic Ly6C+
Yannick Morias1, Chloé Abels1, Damya Laoui1
1Myeloid Cell Immunology Laboratory, Vlaams Instituut voor Biotechnologie (VIB), Brussels, Belgium; Cellular and Molecular Immunology Unit, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Abstract:
Monocytes consist of two well-defined subsets, the Ly6C+ and Ly6C- monocytes. Both CD11b+ myeloid cells populations have been proposed to infiltrate tissues during inflammation. While infiltration of Ly6C+ monocytes is an established pathogenic factor during hepatic inflammation, the role of Ly6C- monocytes remains elusive. Mice suffering experimental African trypanosome infection die from systemic inflammatory response syndrome (SIRS) that is initiated by phagocytosis of parasites by liver myeloid cells and culminates in apoptosis/necrosis of liver myeloid and parenchymal cells that reduces host survival. C57BL/6 mice are considered as trypanotolerant to Trypanosoma congolense infection. We have reported that in these animals, IL-10, produced among others by myeloid cells, limits the liver damage caused by pathogenic TNF-producing Ly6C+ monocytes, ensuring prolonged survival. Here, the heterogeneity and dynamics of liver myeloid cells in T. congolense-infected C57/BL6 mice was further dissected. Moreover, the contribution of Ly6C- monocytes to trypanotolerance was investigated. By using FACS analysis and adoptive transfer experiments, we found that the accumulation of Ly6C- monocytes and macrophages in the liver of infected mice coincided with a drop in the pool of Ly6C+ monocytes. Pathogenic TNF mainly originated from Ly6C+ monocytes while Ly6C- monocytes and macrophages were major and equipotent sources of IL-10 within myeloid cells. Moreover, Nr4a1 (Nur77) transcription factor-dependent Ly6C- monocytes exhibited IL-10-dependent and cell contact-dependent regulatory properties contributing to trypanotolerance by suppressing the production of TNF by Ly6C+ monocytes and by promoting the differentiation of the latter cells into macrophages. Thus, Ly6C- monocytes can dampen liver damage caused by an extensive Ly6C+ monocyte-associated inflammatory immune response in T. congolense trypanotolerant animals. In a more general context, Ly6C- or Ly6C+ monocyte targeting may represent a therapeutic approach in liver pathogenicity induced by chronic infection.
Insights
Ly6C- monocytes protect the liver during African trypanosome infection by producing IL-10 and suppressing inflammatory TNF from Ly6C+ monocytes. This dampens liver damage and promotes trypanotolerance.
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- Monocytes, key immune cells, exist as Ly6C+ and Ly6C- subsets, both implicated in inflammatory tissue infiltration.
- Hepatic inflammation during African trypanosome infection involves pathogenic Ly6C+ monocytes and systemic inflammatory response syndrome (SIRS).
- C57BL/6 mice exhibit trypanotolerance to Trypanosoma congolense, with IL-10 limiting liver damage caused by TNF-producing Ly6C+ monocytes.
Purpose of the Study:
- To investigate the heterogeneity and dynamics of liver myeloid cells during Trypanosoma congolense infection in C57BL/6 mice.
- To elucidate the specific role of Ly6C- monocytes in conferring trypanotolerance.
- To understand the regulatory mechanisms by which Ly6C- monocytes influence the inflammatory response.
Main Methods:
- Flow cytometry (FACS) analysis to characterize liver myeloid cell populations.
- Adoptive transfer experiments to assess monocyte function.
- Investigation of cytokine production (TNF, IL-10) by different monocyte subsets.
- Analysis of transcription factor Nr4a1 (Nur77) and IL-10 dependency.
Main Results:
- Accumulation of Ly6C- monocytes and macrophages in the liver correlated with a decrease in Ly6C+ monocytes during infection.
- Ly6C+ monocytes were the primary source of pathogenic TNF, while Ly6C- monocytes and macrophages produced significant IL-10.
- Nr4a1-dependent Ly6C- monocytes exhibited IL-10-mediated, cell-contact-dependent suppression of TNF production by Ly6C+ monocytes.
- Ly6C- monocytes promoted the differentiation of Ly6C+ monocytes into macrophages.
Conclusions:
- Ly6C- monocytes play a crucial role in dampening liver damage during Trypanosoma congolense infection by regulating Ly6C+ monocyte-driven inflammation.
- These findings highlight the distinct and complementary roles of monocyte subsets in managing parasitic infections and maintaining host tolerance.
- Targeting Ly6C- or Ly6C+ monocyte populations may offer a therapeutic strategy for liver pathologies associated with chronic infections.
