Fate of inflammatory neutrophils within the joint

A. L. Bell, A. E. Irvine1, K. Magill1 and R. McKane2

Musculoskeletal Education and Research Unit and 1Department of Haematology, Queen’s University of Belfast and 2Ulster, North Down and Ards Hospital Trust, Dundonald, Belfast, UK

Correspondence to: A. L. Bell, Arthritis Research Group, Queen’s University of Belfast, Musculoskeletal Education and Research Unit, Musgrave Park Hospital, Stockman’s lane, Belfast BT9 7JB, UK. E-mail: a.bell{at} qub.ac.uk

SIR, We agree with Ottonello et al. [1] that the fate of neutrophils at inflammatory sites, especially within the rheumatoid joint, is an important issue which needs to be clarified. Their study, recently reported in this journal, is one of a very few which examines the influence of inflammatory synovial fluid on apoptosis in neutrophils [1, 2]. In their studies, joint fluid from eight of 11 RA patients produced inhibition of spontaneous and stimulated apoptosis in cultured neutrophils. Evidence is presented that this effect relates to adenosine levels within the joint fluids. The authors suggest that their findings support the view that, within the inflamed rheumatoid joint, synovial fluid factors (especially adenosine) tend to inhibit apoptosis and prolong neutrophil lifespan, thus maintaining the inflammatory response.

Their results appear to conflict with some of our own findings [2] in which we reported that synovial fluids from a variety of arthritic patients generally promoted neutrophil apoptosis, a finding at odds with our own initial hypothesis. We demonstrated a clear dose–response effect using serial dilutions of joint fluid. We pointed out, however, the variability of individual responses between patient samples; indeed some synovial fluid samples caused inhibition or no effect rather than accelerated apoptosis. We studied more than 30 joint fluids and compared effects on autologous and heterologous peripheral blood as well as synovial fluid neutrophils. One important finding from our data, in keeping with other published work [3], was that rates of spontaneous apoptosis found in synovial fluid neutrophils were approximately double those of peripheral blood neutrophils. We interpret this as evidence to support the view that neutrophils within the inflamed joint cavity have been previously exposed to apoptosis-promoting influences, presumably contained in synovial fluid. (Others have shown that, following in vivo treatment of subjects with apoptosis-inhibiting cytokines, blood neutrophil cultures in vitro show retarded apoptosis [4].) Ottonello et al. provide no data in which quantitative comparisons are made of joint fluid and peripheral blood neutrophil responses to synovial fluid.

Our findings on the lack of correlation between cytokine levels and the effect of synovial fluid on neutrophil apoptosis are confirmed in the study of Ottonello et al. The differences between our results and those of Ottonello et al. may well be methodological in origin, reflecting differences in patient selection, drug treatment, sample preparation or neutrophil separation. Equally, they may reflect the variable capacity of synovial fluids to influence neutrophil cell death. This should not be surprising because, although the very fact that joint fluid can be withdrawn indicates inflammation, the process in a single joint may be moving towards either resolution or persistence. One would expect accelerated neutrophil apoptosis in resolving fluids and inhibition in persistently active fluids, given equally efficient macrophage clearance mechanisms. Alternatively, if one accepts that resolution of the neutrophil phase of inflammatory arthritis is mainly due to loss of cellular recruitment, then what happens to the neutrophils already in the joint? Death by necrosis (which ought to cause persistence of inflammation) or clearance through lymphatic channels (for which there is very little evidence) do not offer convincing explanations. We favour the view that rates of apoptosis in inflammatory neutrophils are being continually modulated by death and survival signals in the inflammatory milieu [3]. Clearly, a great deal more work remains to be done to clarify the role of neutrophil apoptosis in inflammatory arthritis.

The authors have declared no conflicts of interest.

References

  1. Ottonello L, Cutolo M, Frumento G et al. Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and proinflammatory cytokines. Rheumatology 2002;41:1241–60
  2. Bell AL, Magill MK, McKane R, Irvine AE. Human blood and synovial fluid neutrophils cultured in vitro undergo programmed cell death which is promoted by the addition of synovial fluid. Ann Rheum Dis 1995;54:910–5[Abstract]
  3. Renshaw SA, Timmons SJ, Eaton V et al. Inflammatory neutrophils retain susceptibility to apoptosis mediated via the Fas death receptor. J Leukoc Biol 2000;67:662–8[Abstract]
  4. Adachi S, Kubota M, Lin YW et al. In vivo administration of granulocyte colony-stimulating factor promotes neutrophil survival in vitro. Eur J Haematol 1994;53:129–34[ISI][Medline]
Accepted 25 February 2003





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