title: Hypoxia: how does the monocyte-macrophage system respond to changes in oxygen availability?
abstract: Hypoxia is an important feature of inflamed tissue, such as the RA joint. Activated monocytes/macrophages and endothelial cells play a pivotal role in the pathogenesis of RA, implicated in the mechanism of inflammation and erosion. During development, myeloid progenitor cells sequentially give rise to monoblasts, promonocytes, and monocytes that are released from the bone marrow into the bloodstream. After extravasation, monocytes differentiate into long-lived, tissue-specific macrophages or DCs. The effect of different oxygen concentrations experienced by these cells during maturation represents a novel aspect of this developmental process. In inflamed joint tissue, the microvascular architecture is highly dysregulated; thus, efficiency of oxygen supply to the synovium is poor. Therefore, invading cells must adapt instantaneously to changes in the oxygen level of the microenvironment. Angiogenesis is an early event in the inflammatory joint, which is important in enabling activated monocytes to enter via endothelial cells by active recruitment to expand the synovium into a "pannus", resulting in cartilage degradation and bone destruction. The increased metabolic turnover of the expanding synovial pannus outpaces the dysfunctional vascular supply, resulting in hypoxia. The abnormal bioenergetics of the microenvironment further promotes synovial cell invasiveness. In RA, joint hypoxia represents a potential threat to cell function and survival. Notably, oxygen availability is a crucial parameter in the cellular energy metabolism, itself an important factor in determining the function of immune cells.
authors.affiliation: 2.Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany. cindy.strehl@charite.de.
authors.forename: Cindy
authors.initials: C
authors.lastname: Strehl
authors.forename: Monique
authors.initials: M
authors.lastname: Fangradt
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
authors.forename: Timo
authors.initials: T
authors.lastname: Gaber
authors.forename: Frank
authors.initials: F
authors.lastname: Buttgereit
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000503:physiopathology; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D009000:Monocytes / Q000187:drug effects / Q000473:pathology*; D010100:Oxygen / Q000494:pharmacology*
chemical_list: D010100:Oxygen
keywords: HIF-1α; HIF-2α; blood; bone marrow; maturation; tissue