Hypoxia, Hypoxia-Inducible Factor-1α, and Innate Antileishmanial Immune Responses

Valentin Schatz,Jonathan Jantsch,Franz Rieger,Patrick Neubert

doi:10.3389/fimmu.2018.00216

Valentin Schatz, Jonathan Jantsch + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2018.00216

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Abstract

Low oxygen environments and accumulation of hypoxia-inducible factors (HIFs) are features of infected and inflamed tissues. Here, we summarize our current knowledge on oxygen levels found in Leishmania-infected tissues and discuss which mechanisms potentially contribute to local tissue oxygenation in leishmanial lesions. Moreover, we review the role of hypoxia and HIF-1 on innate antileishmanial immune responses.

Highlights

Low oxygen (O2) environments are a key feature of infected and inflamed tissue
Prolylhydroxylase domain (PHD) enzymes play a key role in the regulation of hypoxia-inducible factors (HIFs)-1α and HIF-2α since oxygen is a critical substrate for the PHD enzymes
We will summarize the evidence of hypoxia and the transcription factors (TFs) HIF-1α and its impact on innate immune responses directed against infection with Leishmania major, Leishmania amazonensis, and Leishmania donovani, which are able to cause cutaneous, mucocutaneous and systemic diseases, respectively (Table 1)

Summary

INTRODUCTION

Low oxygen (O2) environments are a key feature of infected and inflamed tissue. Several lines of evidence demonstrate that oxygen levels of afflicted tissues are much lower than these currently used in standard cell culture experiments and, in general, correspond to values below 4% O2 [reviewed in Ref. [1, 2]] Low oxygen levels are able to incapacitate oxygen-dependent antimicrobial effector enzymes such as the phagocytes oxidase or inducible NO synthase which both require oxygen as cosubstrate in order to produce their antimicrobial reactive oxygen species (ROS) and reactive nitrogen species (RNS) [reviewed in Ref. [1, 2]]. Hypoxia is a state of reduced availability of oxygen and in addition induces a transcriptional response, which is governed by the transcription factors (TFs) hypoxia-inducible factor (HIF)-1 and HIF-2 Both TFs belong to the basic helix–loop–helix-PAS family of TF, consisting of HIF-1α or HIF-2α and its dimerization partner aryl hydrocarbon receptor nuclear translocator (ARNT) [reviewed in Ref. Normoxic, inflammatory HIF-1α stabilization is closely linked to nuclear factor (NF)-κB activation [12, 13], and involves transcriptional and posttranslational signaling events [14,15,16]. These findings demonstrate that hypoxic and inflammatory responses are intertwined. We will summarize the evidence of hypoxia and the TF HIF-1α and its impact on innate immune responses directed against infection with Leishmania major, Leishmania amazonensis, and Leishmania donovani, which are able to cause cutaneous, mucocutaneous and systemic (visceral) diseases, respectively (Table 1)

OXYGEN LEVEL IN LEISHMANIAL

Potential Factors Regulating Tissue

Findings

Internalization of Leishmania and Hypoxia