Hypoxia Inducible Factor-1α in Astrocytes and/or Myeloid Cells Is Not Required for the Development of Autoimmune Demyelinating Disease

Natacha Le Moan,Pamela E Rios Coronado,Katerina Akassoglou,Victoria A Rafalski,Jae Kyu Ryu,Catherine Bedard,Kim M Baeten,Catriona Syme,Dimitrios Davalos

doi:10.1523/eneuro.0050-14.2015

Natacha Le Moan, Pamela E Rios Coronado + Show 7 more

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https://doi.org/10.1523/eneuro.0050-14.2015

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Journal: eneuro	Publication Date: Mar 1, 2015
Citations: 31	License type: cc-by

Affiliation: Gladstone Institutes, University of California System

Abstract

Hypoxia-like tissue alterations, characterized by the upregulation of hypoxia-inducible factor-1α (HIF-1α), have been described in the normal appearing white matter and pre-demyelinating lesions of multiple sclerosis (MS) patients. As HIF-1α regulates the transcription of a wide set of genes involved in neuroprotection and neuroinflammation, HIF-1α expression may contribute to the pathogenesis of inflammatory demyelination. To test this hypothesis, we analyzed the effect of cell-specific genetic ablation or overexpression of HIF-1α on the onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. HIF-1α was mainly expressed in astrocytes and microglia/macrophages in the mouse spinal cord at the peak of EAE. However, genetic ablation of HIF-1α in astrocytes and/or myeloid cells did not ameliorate clinical symptoms. Furthermore, conditional knock-out of Von Hippel Lindau, a negative regulator of HIF-1α stabilization, failed to exacerbate the clinical course of EAE. In accordance with clinical symptoms, genetic ablation or overexpression of HIF-1α did not change the extent of spinal cord inflammation and demyelination. Overall, our data indicate that despite dramatic upregulation of HIF-1α in astrocytes and myeloid cells in EAE, HIF-1α expression in these two cell types is not required for the development of inflammatory demyelination. Despite numerous reports indicating HIF-1α expression in glia, neurons, and inflammatory cells in the CNS of MS patients, the cell-specific contribution of HIF-1α to disease pathogenesis remains unclear. Here we show that although HIF-1α is dramatically upregulated in astrocytes and myeloid cells in EAE, cell-specific depletion of HIF-1α in these two cell types surprisingly does not affect the development of neuroinflammatory disease. Together with two recently published studies showing a role for oligodendrocyte-specific HIF-1α in myelination and T-cell-specific HIF-1α in EAE, our results demonstrate a tightly regulated cellular specificity for HIF-1α contribution in nervous system pathogenesis.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the nervous system characterized by inflammation, gliosis, destruction of myelin sheaths, and axonal damage leading to permanent functional deficits (Brück and Stadelmann, 2005)
We crossed hypoxia-inducible factor-1␣ (HIF-1␣)fl/fl mice with mice expressing the cre recombinase driven by the lysozyme M promoter or the glial fibrillary acidic protein (GFAP) promoter (GFAP-Cre; Bajenaru et al, 2002) to generate cell-specific depletion of HIF-1␣ in microglia/macrophages or astrocytes respectively. lysM-Cre mice were crossed with VHLfl/fl to generate cell-specific overexpression of HIF-1␣ in the myeloid lineage
HIF-1␣ RNA levels were ϳ1.5-fold higher at the peak of EAE (Fig. 1B), suggesting that HIF-1␣ expression is mainly regulated at the protein rather than the transcriptional level

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the nervous system characterized by inflammation, gliosis, destruction of myelin sheaths, and axonal damage leading to permanent functional deficits (Brück and Stadelmann, 2005). Hypoxia-like tissue alterations, predominantly characterized by the accumulation of the hypoxia-inducible factor-1␣ (HIF-1␣), occur at a very early stage in MS pathogenesis (Aboul-Enein et al, 2003; Graumann et al, 2003; Lassmann, 2003; Stadelmann et al, 2005; Marik et al, 2007; Zeis et al, 2008). HIF-1␣ is upregulated in pre-demyelinating lesions and normal appearing white matter (NAWM) of MS patients (Graumann et al, 2003; Zeis et al, 2008). Determining the early hypoxic events leading to the formation of demyelinating lesions and their causative role in the pathology is crucial to better understand MS pathogenesis and discover novel targets and strategies for therapeutic intervention

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