Neutrophil apoptosis in rheumatoid arthritis is regulated by local oxygen tensions within joints.
Neutrophils are normally short-lived cells and die by apoptosis, but when recruited into tissues, their apoptosis is delayed, and they survive for much longer time periods. In inflammatory diseases, such as rheumatoid arthritis (RA), this delayed apoptosis may lead to increased tissue damage and a failure of the inflammation to resolve. However, there are conflicting reports in the literature as to whether neutrophil apoptosis is delayed or accelerated in rheumatoid joints. In this report, we show that neutrophils isolated from the synovial fluid (SF) of patients with RA show accelerated rates of apoptosis when incubated ex vivo and that SF, despite containing a variety of antiapoptotic cytokines, is proapoptotic. Paradoxically, levels of the key neutrophil survival protein Mcl-1 are elevated in freshly isolated SF neutrophils compared with matched peripheral blood samples from the same patients, indicating that delayed neutrophil apoptosis has been signaled in vivo as the cells enter the joints. However, when SF was added to neutrophils and incubated under hypoxia (1% O(2)), conditions known to exist in vivo within joints, the SF was antiapoptotic. These data reveal that the rheumatoid synovial joint contains a complex mixture of pro- and antiapoptotic factors and that the low, local oxygen tensions that exist within these joints can exert profound effects on neutrophil survival. These experiments also highlight the importance of performing in vitro experiments under laboratory conditions that closely mimic those that occur in vivo; otherwise, misleading conclusions may be drawn.
Cross
Andrew
A
Department of Medicine, School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, UK.
Barnes
Theresa
T
Bucknall
Roger C
RC
Edwards
Steven W
SW
Moots
Robert J
RJ
D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D006801:Humans; D000860:Hypoxia / Q000276:immunology; D007596:Joints / Q000276:immunology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D010100:Oxygen / Q000276:immunology* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology*; D013582:Synovial Fluid / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000276:immunology
C494826:BAX protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D010100:Oxygen