CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis
Norikuni Kawanaka1, Masahiro Yamamura, Tetsushi Aita
1Department of Medicine and Clinical Science, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Objective:
CD14+,CD16+ monocytes, identified as a minor population of monocytes in human peripheral blood (PB), have been implicated in several inflammatory diseases. We undertook this study to investigate the relevance of this phenotype to joint inflammation in rheumatoid arthritis (RA).
Methods:
The expression of CD14, CD16, CC chemokine receptor 1 (CCR1), CCR5, and intercellular adhesion molecule 1 (ICAM-1) on monocytes was measured by flow cytometric analysis. Concentrations of the cytokines known to induce CD16 (including transforming growth factor beta1 [TGFbeta1], macrophage colony-stimulating factor [M-CSF], and interleukin-10 [IL-10]) and concentrations of the soluble form of CD14 (sCD14) in plasma and synovial fluid (SF) samples were measured by enzyme-linked immunosorbent assay. The induction of CD16 on RA blood monocytes cultured for 18 hours with 1 or with all 3 cytokines was determined.
Results:
The mean +/- SD frequency of CD14+,CD16+ blood monocytes was significantly increased in RA patients (11.7 +/- 5.6%; n = 105) compared with healthy controls (9.5 +/- 2.2%; n = 15) (P < 0.01), and the patient group with an increased frequency of CD16+ monocytes (> or =13.9%) had active disease, as defined by increased counts of tender and swollen joints, levels of acute-phase reactants, and titers of rheumatoid factor. The response to drug therapy correlated with changes in the frequency of this phenotype. The expression of CD16 on SF monocytes from RA patients was markedly elevated compared with the expression on PB monocytes. CD16 expression on RA blood monocytes was augmented in vitro by IL-10, M-CSF, and TGFbeta1. Plasma concentrations of these cytokines and of sCD14 were significantly higher in RA patients with high CD16+ monocyte frequencies than in those with low CD16+ monocyte frequencies or in healthy controls. CD14+,CD16+ monocytes expressed higher levels of CCR1, CCR5, and ICAM-1 than did regular CD14++,CD16- monocytes, particularly in active RA.
Conclusion:
These results indicate that the maturation of blood monocytes into tissue-infiltrative CD16+ cells before entry into the joint, induced by cytokine spillover from the inflamed joint, may contribute to the persistent joint inflammation of RA.
Insights
CD14+,CD16+ monocytes are elevated in rheumatoid arthritis (RA) patients, correlating with disease activity. Cytokine-induced maturation of these monocytes may drive persistent joint inflammation in RA.
Area of Science:
- Immunology
- Rheumatology
Background:
- CD14+,CD16+ monocytes are a minor subset in human peripheral blood (PB).
- This monocyte subset has been implicated in various inflammatory diseases.
Purpose of the Study:
- To investigate the role of CD14+,CD16+ monocytes in joint inflammation in rheumatoid arthritis (RA).
Main Methods:
- Flow cytometry measured CD14, CD16, CCR1, CCR5, and ICAM-1 expression on monocytes.
- ELISA measured cytokine concentrations (TGF-beta1, M-CSF, IL-10) and soluble CD14 (sCD14).
- In vitro culture assessed CD16 induction on RA monocytes by cytokines.
Main Results:
- RA patients showed a significantly higher frequency of CD14+,CD16+ blood monocytes compared to healthy controls.
- Increased CD16+ monocyte frequency correlated with active RA disease markers and higher cytokine/sCD14 levels.
- CD14+,CD16+ monocytes expressed higher levels of CCR1, CCR5, and ICAM-1, particularly in active RA.
Conclusions:
- Elevated CD14+,CD16+ monocytes in RA patients suggest their involvement in disease pathogenesis.
- Cytokine-induced maturation of monocytes before joint entry may contribute to persistent RA joint inflammation.
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