Inflammation is part of the normal response to infection or injury, but prolonged inflammatory activity can cause diseases such as arthritis or Crohn's disease. In a study published in the March 7th issue of Cell, scientists report that inflammation can be prevented in mice by blocking the glycolytic metabolic pathway in macrophages and neutrophils used in hypoxic, or low oxygen, conditions.

Part of the inflammatory response involves the massive migration of these immune cells out of circulation to the site of tissue injury. One of the signals that guides the cells is the hypoxia that arises when the blood vessels at the wound site are disrupted. A protein called hypoxia inducible transcription factor-1α (HIF1α) is known to be essential for hypoxia-induced increases in glycolysis in some tissues, enabling cells to function in damaged tissues by utilizing the glycolytic pathway to generate ATP.

The authors created a targeted deletion of the HIF1α transcription factor in macrophages and neutrophils, and under hypoxic conditions the cellular ATP pool in these HIF1α-deficient cells was drastically reduced, confirming that HIF1α is essential for the regulation of glycolytic capacity in these cells. The metabolic defect also renders these cells incapable of aggregation, motility and invasiveness, and reduces their ability to kill bacteria, all crucial components of an effective inflammatory response. When mice lacking HIF1α were subjected to an arthritis-inducing stimulus, they did not develop joint swelling or other inflammatory symptoms. The authors also showed that the loss of Von Hippel Lindau, an HIF1α negative regulator and tumour suppressor, causes a hyperinflammatory response. These data indicate that HIF1α lies in a crucial position in the inflammatory pathway and that appropriate agonists or antagonists could either boost or block inflammatory activity, respectively. Interestingly, the loss of HIF1α compared with the loss of vascular endothelial growth factor, a downstream target of HIF1α, results in somewhat different phenotypes, indicating that the functions of the two molecules only partially overlap.

A large number of HIF1α inhibitors are being developed for the treatment of cancer, as high levels of HIF1α expression are seen in some tumours and because of HIF1α involvement in angiogenesis. These drugs might turn out to have an even bigger market in treating inflammation and arthritis because they would have an advantage over present treatments, as they can completely block tissue invasion by inflammatory cells in animal models.