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

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