Activation of hypoxia-inducible factor 1 attenuates periapical inflammation and bone loss

Hypoxia (low oxygen level) is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation of hypoxia-inducible factor 1 (HIF-1). Hypoxia interferes degradation of HIF-1 alpha subunit (HIF-1α), leading to stabilisation of HIF-1α, heterodimerization with HIF-1 beta subunit (HIF-1β) and subsequent activation of HIF-1 pathway. Apical periodontitis (periapical lesion) is a consequence of endodontic infection and ultimately results in destruction of tooth-supporting tissue, including alveolar bone. Thus far, the role of HIF-1 in periapical lesions has not been systematically examined. In the present study, we determined the role of HIF-1 in a well-characterised mouse periapical lesion model using two HIF-1α-activating strategies, dimethyloxalylglycine (DMOG) and adenovirus-induced constitutively active HIF-1α (CA-HIF1A). Both DMOG and CA-HIF1A attenuated periapical inflammation and tissue destruction. The attenuation in vivo was associated with downregulation of nuclear factor-κappa B (NF-κB) and osteoclastic gene expressions. These two agents also suppressed NF-κB activation and subsequent production of proinflammatory cytokines by macrophages. Furthermore, activation of HIF-1α by DMOG specifically suppressed lipopolysaccharide-stimulated macrophage differentiation into M1 cells, increasing the ratio of M2 macrophages against M1 cells. Taken together, our data indicated that activation of HIF-1 plays a protective role in the development of apical periodontitis via downregulation of NF-κB, proinflammatory cytokines, M1 macrophages and osteoclastogenesis. A breath of life for root lesions Targeting a protein complex involved in the body’s response to low internal oxygen concentrations could help treat destructive tooth root inflammations. Hajime Sasaki from the University of Michigan and colleagues in the U.S. and Japan investigated the role of the protein complex HIF-1 in oral inflammation. They induced lesions in the root area of molar teeth in mice, exposing them to oral bacteria, which led to inflammation. They injected the mice with one of two agents that activate the HIF-1 pathway. Inflammation and bone destruction in the lesions were both reduced. Activation of the HIF-1 pathway turned off another pathway, called NF-κB, involved in the immune response to infection. It also turned off genes involved in bone destruction. The results