Interdependence of hypoxic and innate immune responses

Abstract

Hypoxia-inducible transcription factor (HIF) is a major regulator of cellular metabolism and adaptation to cellular stress caused by oxygen deficiency (hypoxia). Phagocytic cells have an essential role in innate immune defense against pathogens; and this is a battle that takes place mainly in the hypoxic microenvironments of infected tissues. It has now become clear that HIF promotes the bactericidal activities of phagocytic cells and supports the innate immune functions of dendritic cells, mast cells and epithelial cells. In response to microbial pathogens, HIF expression is upregulated through pathways involving the key immune response regulator nuclear factor-κB, highlighting an interdependence of the innate immune and hypoxic responses to infection and tissue damage. In turn, HIF-driven innate immune responses have important consequences for both the pathogen and the host, and its central role in immune defence demonstrates the importance of the tissue microenvironment in controlling infectious disease.

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…Chronic inflammation also contributes to the local deficiency of oxygen due to the combination of reduced circulation at inflammatory sites and increased metabolic demand from infiltrating immune cells. In a feed-forward manner, hypoxia can promote chronic inflammation and thus, itself, in the developing TME through activation of NF-κB signaling in macrophages, neutrophils and non-immune cells, a finding recently confirmed in vivo in the lungs of mice [65,66].…”

Hydroxylases as therapeutic targets in inflammatory bowel disease

“…As well as having a central role in the adaptive response to hypoxia, HIF has more recently been appreciated as a key regulator of innate immunity and inflammation. 28,36,37 Indeed, conditional knockout of the HIF-1a isoform has revealed a key role for HIF in mediating functional immune responses in macrophages, dendritic cells, T-cells and neutrophils. [38][39][40][41][42] The expression of hypoxia-inducible transcription factors such as HIF in mucosal tissue has been demonstrated to be increased in diseases of the GI tract including celiac disease 43 and IBD.…”

Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function

“…As such, PHDs may be an effective target for therapeutic manipulation (1,5). It has recently become clear that hydroxylase activity can impact upon the development of inflammation and that hydroxylase inhibitors may represent a novel therapeutic approach in chronic inflammatory disease (5,6).…”