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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adenosine Triphosphate / metabolism
-
Animals
-
Arthritis / genetics
-
Arthritis / immunology
-
Cell Aggregation / genetics
-
Cell Movement / genetics
-
Chemotaxis, Leukocyte / genetics
-
Chemotaxis, Leukocyte / immunology*
-
Endothelial Growth Factors / deficiency
-
Endothelial Growth Factors / genetics
-
Energy Metabolism / genetics
-
Female
-
Hypoxia / genetics
-
Hypoxia / immunology
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
Immunity / genetics
-
Immunity / immunology*
-
Inflammation / genetics
-
Inflammation / immunology*
-
Intercellular Signaling Peptides and Proteins / deficiency
-
Intercellular Signaling Peptides and Proteins / genetics
-
Ligases / genetics
-
Ligases / immunology
-
Lymphokines / deficiency
-
Lymphokines / genetics
-
Macrophages / immunology
-
Macrophages / metabolism
-
Male
-
Mice
-
Mice, Knockout
-
Myeloid Cells / immunology*
-
Myeloid Cells / metabolism
-
Neutrophils / immunology
-
Neutrophils / metabolism
-
Phagocytosis / genetics
-
Phagocytosis / immunology
-
Transcription Factors / genetics
-
Transcription Factors / immunology*
-
Tumor Suppressor Proteins*
-
Ubiquitin-Protein Ligases*
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors
-
Von Hippel-Lindau Tumor Suppressor Protein
Substances
-
Endothelial Growth Factors
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
Intercellular Signaling Peptides and Proteins
-
Lymphokines
-
Transcription Factors
-
Tumor Suppressor Proteins
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors
-
Adenosine Triphosphate
-
Ubiquitin-Protein Ligases
-
Von Hippel-Lindau Tumor Suppressor Protein
-
Ligases