title: Hypoxia Inducible Factor-1αin Astrocytes and/or Myeloid Cells Is Not Required for the Development of Autoimmune Demyelinating Disease
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-1αregulates the transcription of a wide set of genes involved in neuroprotection and neuroinflammation, HIF-1αexpression 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-1αon the onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. HIF-1αwas mainly expressed in astrocytes and microglia/macrophages in the mouse spinal cord at the peak of EAE. However, genetic ablation of HIF-1αin astrocytes and/or myeloid cells did not ameliorate clinical symptoms. Furthermore, conditional knock-out of Von Hippel Lindau, a negative regulator of HIF-1αstabilization, failed to exacerbate the clinical course of EAE. In accordance with clinical symptoms, genetic ablation or overexpression of HIF-1αdid not change the extent of spinal cord inflammation and demyelination. Overall, our data indicate that despite dramatic upregulation of HIF-1αin astrocytes and myeloid cells in EAE, HIF-1αexpression in these two cell types is not required for the development of inflammatory demyelination. Despite numerous reports indicating HIF-1αexpression in glia, neurons, and inflammatory cells in the CNS of MS patients, the cell-specific contribution of HIF-1αto disease pathogenesis remains unclear. Here we show that although HIF-1αis dramatically upregulated in astrocytes and myeloid cells in EAE, cell-specific depletion of HIF-1αin 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-1αin myelination and T-cell-specific HIF-1αin EAE, our results demonstrate a tightly regulated cellular specificity for HIF-1αcontribution in nervous system pathogenesis.
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Natacha
authors.initials: N
authors.lastname: Le Moan
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Baeten
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Rafalski
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jae Kyu
authors.initials: JK
authors.lastname: Ryu
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Rios Coronado
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bedard
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Catriona
authors.initials: C
authors.lastname: Syme
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Davalos
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA ; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
keywords: EAE; HIF-1alpha; astrocytes; cre/loxP; macrophages; neuroinflammation