Long-Term Exposure to Inflammation Induces Differential Cytokine Patterns and Apoptosis in Dendritic Cells.

Laura Stentoft Carstensen,Morten Hansen,Olivia Lie-Andersen,Inge Marie Svane,Andreas Obers,Michael Douglas Crowther

doi:10.3389/fimmu.2019.02702

Laura Stentoft Carstensen, Morten Hansen + Show 4 more

Open Access

https://doi.org/10.3389/fimmu.2019.02702

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Abstract

The activation of dendritic cells (DCs) has profound implications and governs the control of adaptive immunity. However, long-term activation might drive exhaustion of immune cells and negatively affect functionality. Here, long-term vs. short-term exposure to bacterial lipopolysaccharide and interferon (IFN)γ was evaluated on human monocyte-derived DCs. Long-term activated DC1s began to undergo apoptosis concomitant with a profound TAM-receptor and efferocytosis-dependent induction of interleukin (IL)-10. Whereas, levels of IL-12p70 and IL-10 were positively correlated upon short-term activation, an inverse association occured upon long-term activation and, while short-term activated CD1a+ DCs were main producers of IL-12p70, CD1a− DCs were the main fraction that underwent apoptosis and released IL-10 upon long-term activation. Moreover, pre-apoptotic long-term activated DCs were no longer able to activate alloreactive IFNγ-responsive T cells present in peripheral blood mononuclear cells from healthy volunteers. The IFNγ response was mediated by IL-12p70, as a strong reduction in IFNγ was observed following blockade with an IL-12p70 neutralizing antibody. Finally, multiplex analysis of DC supernatants revealed a particular pattern of proteins associated with apoptosis, cancer and chronic inflammation partly overlapping with gold standard DCs well-known for their inability to secrete IL-12p70. In conclusion, long-term activated DC1s significantly changed their profile toward a non-functional, tumor-promoting and anti-inflammatory phenotype.

Highlights

Dendritic cells (DCs) are antigen-presenting cells that primarily process and present antigens to T cells
No significant differences between the levels of IL-12p70 measured on day 1, 2, and 3 were observed (Figure 1A) and whereas the absolute levels of IL-12p70 varied from donor to donor, the kinetics were equivalent among donors (Figure S1A)
Additional ELISA analysis of IL-12p40, IL-23, TNFα, and IL6 from DC supernatants aligned with IL-12p70 in terms of decreasing levels observed in supernatants from four-day DC1s albeit in the case of TNFα and especially IL-6 at less striking changes (Figures S1C–F)

Summary

Introduction

Dendritic cells (DCs) are antigen-presenting cells that primarily process and present antigens to T cells. DCs bridge the innate and adaptive immune system and play a vital role in generation of both immunity and tolerance [1]. Immature DCs are specialized in antigen uptake and processing. They are activated by pathogen-derived molecular patterns or danger-associated molecular patterns on dying, stressed, or injured host cells resulting in inflammation and perturbed tissue homeostasis [2]. Lipopolysaccharide (LPS) constitutes a classical pathogen-derived molecular pattern activating DCs via Toll-Like receptor 4 [3]. Strong synergy is provided by interferon (IFN)γ

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