The Trypanosoma brucei-Derived Ketoacids, Indole Pyruvate and Hydroxyphenylpyruvate, Induce HO-1 Expression and Suppress Inflammatory Responses in Human Dendritic Cells.

Hannah K Fitzgerald,Glen A Doherty,Aisling Dunne,Eva Desmond,Derek P Nolan,Jayne Doherty,Michael G Monaghan,Nuno G B Neto,Sinead A O’Rourke,Miriam Tosetto,Jean M Fletcher,Elizabeth J Ryan

doi:10.3390/antiox11010164

Abstract

The extracellular parasite and causative agent of African sleeping sickness Trypanosoma brucei (T. brucei) has evolved a number of strategies to avoid immune detection in the host. One recently described mechanism involves the conversion of host-derived amino acids to aromatic ketoacids, which are detected at relatively high concentrations in the bloodstream of infected individuals. These ketoacids have been shown to directly suppress inflammatory responses in murine immune cells, as well as acting as potent inducers of the stress response enzyme, heme oxygenase 1 (HO-1), which has proven anti-inflammatory properties. The aim of this study was to investigate the immunomodulatory properties of the T. brucei-derived ketoacids in primary human immune cells and further examine their potential as a therapy for inflammatory diseases. We report that the T. brucei-derived ketoacids, indole pyruvate (IP) and hydroxyphenylpyruvate (HPP), induce HO-1 expression through Nrf2 activation in human dendritic cells (DC). They also limit DC maturation and suppress the production of pro-inflammatory cytokines, which, in turn, leads to a reduced capacity to differentiate adaptive CD4+ T cells. Furthermore, the ketoacids are capable of modulating DC cellular metabolism and suppressing the inflammatory profile of cells isolated from patients with inflammatory bowel disease. This study therefore not only provides further evidence of the immune-evasion mechanisms employed by T. brucei, but also supports further exploration of this new class of HO-1 inducers as potential therapeutics for the treatment of inflammatory conditions.

Highlights

Infection of the mammalian vasculature and central nervous system (CNS) with the extracellular protozoan parasite Trypanosoma brucei (T. brucei) can lead to fatal human sleeping sickness, known as African trypanosomiasis
We have previously shown that HPP and indole pyruvate (IP) are capable of inducing heme oxygenase-1 (HO-1), as well as having immunomodulatory effects, in murine macrophages and glia [5]
dendritic cells (DC) were treated with HPP or IP (500–1000 μM) for 24 h

Summary

Introduction

Infection of the mammalian vasculature and central nervous system (CNS) with the extracellular protozoan parasite Trypanosoma brucei (T. brucei) can lead to fatal human sleeping sickness, known as African trypanosomiasis. IP and HPP are potent inducers of the immunosuppressive enzyme heme oxygenase-1 (HO-1) in murine glia and macrophages [5]. This occurs in a nuclear factor (erythroid-derived 2)-like 2 (Nrf2) dependent manner and leads to a reduction in LPSinduced pro-inflammatory cytokines and innate immune cell maturation. HO-1 has well established anti-inflammatory properties and is induced by a vast number of stimuli during oxidative stress and inflammation. The potent anti-inflammatory properties of HO-1 are underlined by rare HO-deficiencies in humans and HO-1 knockout mice, which, along with the expected sensitivity to oxidative stress, show high levels of chronic inflammation [11,12,13]. Induction of HO-1 with known and novel HO-1 inducers is being explored as a therapy for a number of autoimmune and inflammatory diseases and we have recently reviewed this in detail elsewhere [14]

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