HIF-1alpha is essential for myeloid cell-mediated inflammation.
Journal: 2003/May - Cell
ISSN: 0092-8674
PUBMED: 12628185
Abstract:
Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment.
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HIF-1α Is Essential for Myeloid Cell-Mediated Inflammation

+5 authors
Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093
Rheumatology Division, Department of Medicine, University of California, San Diego, La Jolla, California 92093
Division of Infectious Diseases, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093
Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 80290 München, Germany
Department of Immunology, Scripps Research Institute, San Diego, California 92037
Renal Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Genentech, Inc., South San Francisco, California 94080
Correspondence: ude.dscu@nosnhojsr

Summary

Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1α, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1α is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1α is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1α is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1α demonstrates its direct regulation of survival and function in the inflammatory microenvironment.

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