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. 2010;12(5):R168.
doi: 10.1186/ar3128. Epub 2010 Sep 9.

Borrelia burgdorferi stimulation of chemokine secretion by cells of monocyte lineage in patients with Lyme arthritis

Junghee J Shin  1 , Klemen Strle, Lisa J Glickstein, Andrew D Luster, Allen C Steere
Affiliations

Borrelia burgdorferi stimulation of chemokine secretion by cells of monocyte lineage in patients with Lyme arthritis

Junghee J Shin et al. Arthritis Res Ther. 2010.

Abstract

Introduction: Joint fluid in patients with Lyme arthritis often contains high levels of CCL4 and CCL2, which are chemoattractants for monocytes and some T cells, and CXCL9 and CXCL10, which are chemoattractants for CD4+ and CD8+ T effector cells. These chemokines are produced primarily by cells of monocyte lineage in TH1-type immune responses. Our goal was to begin to learn how infection with Borrelia burgdorferi leads to the secretion of these chemokines, using patient cell samples. We hypothesized that B. burgdorferi stimulates chemokine secretion from monocytes/macrophages in multiple ways, thereby linking innate and adaptive immune responses.

Methods: Peripheral blood mononuclear cells (PBMC) from 24 Lyme arthritis patients were stimulated with B. burgdorferi, interferon (IFN)-γ, or both, and the levels of CCL4, CCL2, CXCL9 and CXCL10 were measured in culture supernatants. CD14+ monocytes/macrophages from PBMC and synovial fluid mononuclear cells (SFMC) were stimulated in the same way, using available samples. CXCR3, the receptor for CXCL9 and CXCL10, and CCR5, the receptor for CCL4, were assessed on T cells from PBMC and SFMC.

Results: In patients with Lyme arthritis, B. burgdorferi but not IFN-γ induced PBMC to secrete CCL4 and CCL2, and B. burgdorferi and IFN-γ each stimulated the production of CXCL9 and CXCL10. However, with the CD14+ cell fraction, B. burgdorferi alone stimulated the secretion of CCL4; B. burgdorferi and IFN-γ together induced CCL2 secretion, and IFN-γ alone stimulated the secretion of CXCL9 and CXCL10. The percentage of T cells expressing CXCR3 or CCR5 was significantly greater in SFMC than PBMC, confirming that TH1 effector cells were recruited to inflamed joints. However, when stimulated with B. burgdorferi or IFN-γ, SFMC and PBMC responded similarly.

Conclusions: B. burgdorferi stimulates PBMC or CD14+ monocytes/macrophages directly to secrete CCL4, but spirochetal stimulation of other intermediate cells, which are present in PBMC, is required to induce CD14+ cells to secrete CCL2, CXCL9 and CXCL10. We conclude that B. burgdorferi stimulates monocytes/macrophages directly and indirectly to guide innate and adaptive immune responses in patients with Lyme arthritis.

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Figures

Figure 1
Figure 1
Secretion of chemokines by peripheral blood mononuclear cells (a) or CD14+ monocytes/macrophages (b) from four normal control subjects. Cells were not stimulated, or they were stimulated with Borrelia burgdorferi or interferon-gamma (IFN-γ) or both. After 5 days of incubation, the levels of chemokines were measured in the culture supernatants. Each point represents the value of an individual control subject. The horizontal bars represent the median values. The highest value for CXCL9 was off the scale and is shown numerically. None of the differences between groups was statistically significant.
Figure 2
Figure 2
Secretion of chemokines by peripheral blood mononuclear cells (a) or CD14+ monocytes/macrophages (b) from 24 patients with Lyme arthritis. Cells were not stimulated, or they were stimulated with Borrelia burgdorferi or interferon-gamma (IFN-γ) or both. After 5 days of incubation, the levels of chemokines were measured in the culture supernatants. Each point represents the value of an individual patient. The horizontal bars represent the median values. The highest values for CXCL9 were off the scale and are shown numerically. All significant differences among stimulated and unstimulated cells are shown in brackets and had a P value of less than 0.001.
Figure 3
Figure 3
The secretion of chemokines secreted by unstimulated or Borrelia burgdorferi- or interferon-gamma (IFN-γ)-stimulated peripheral blood mononuclear cells (PBMCs) or synovial fluid mononuclear cells (SFMCs) from 11 patients with Lyme arthritis. After 5 days of incubation, the levels of chemokines were measured in the cell supernatants. The horizontal bars represent the median values. The highest values for CXCL9 were off the scale and are shown numerically. With each stimulus, chemokine levels did not differ significantly between PBMCs and SFMCs.
Figure 4
Figure 4
The expression of the chemokine receptors CXCR3 and CCR5 on unstimulated or Borrelia burgdorferi- or interferon-gamma (IFN-γ)-stimulated peripheral blood mononuclear cells (PBMCs) or synovial fluid mononuclear cells (SFMCs) from six patients with Lyme arthritis. (a) The flow cytometry data are shown for the PBMCs of one patient. After 5 days of incubation, nonadherent cells were resuspended, collected, and stained with antibodies. A forward scatter/side scatter (FSC/SSC) gate (R1) was used to exclude dead cells, and a CD3/CD4 gate (R2) was used to further restrict analysis to T cells. The number of events in each gate per number of events collected or the percentage of gated cells positive for CXCR3 or CCR5 is indicated on the histograms. (b) The percentages of T cells that were brighter than the isotype control are shown. The horizontal bars represent the median values. Significant differences between PBMCs and SFMCs are shown in brackets.
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