HIF-1alpha is essential for myeloid cell-mediated inflammation.

Cramer T, Yamanishi Y, Clausen BE, Förster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS
Cell. 2003 112 (5): 645-57

PMID: 12628185 · PMCID: PMC4480774 · DOI:10.1016/s0092-8674(03)00154-5

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.

MeSH Terms (29)

Adenosine Triphosphate Animals Arthritis Cell Aggregation Cell Movement Chemotaxis, Leukocyte Endothelial Growth Factors Energy Metabolism Female Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit Immunity Inflammation Intercellular Signaling Peptides and Proteins Ligases Lymphokines Macrophages Male Mice Mice, Knockout Myeloid Cells Neutrophils Phagocytosis Transcription Factors Tumor Suppressor Proteins Ubiquitin-Protein Ligases Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Von Hippel-Lindau Tumor Suppressor Protein

Connections (1)

This publication is referenced by other Labnodes entities:

Links