Novel insights in the regulation of CCL18 secretion by monocytes and dendritic cells via cytokines, Toll-like receptors and rheumatoid synovial fluid

BACKGROUND: The T cell attracting chemokine CCL18 is produced by antigen presenting cells and a role for CCL18 has been suggested in the pathogenesis of a variety of diseases. Rheumatoid arthritis (RA) is one of these conditions, in which abundant CCL18 production is present. Although Th2 cytokines and IL-10 are known to have an effect on CCL18 production, there are several gaps in our knowledge regarding the exact regulation of CCL18 secretion, both in general and in RA. In this study we provide new insights in the regulation of CCL18 secretion by monocytes and dendritic cells. RESULTS: In contrast to a large panel of pro-inflammatory stimuli (IL-1β, TNF-α, IL-10, IL-13, IL-15, IL-17, IL-18, IFN-γ), T cell mimicking molecules (RANKL, CD40L) or TLR driven maturation, the anti-inflammatory IL-10 strongly stimulated DC to secrete CCL18. On freshly isolated monocytes, CCL18 secretion was induced by IL-4 and IL-13, in strong synergy with IL-10. This synergistic effect could already be observed after only 24 hours, indicating that not only macrophages and dendritic cells, but also monocytes secrete CCL18 under these stimulatory conditions. A high CCL18 expression was detected in RA synovial tissue and incubation of monocytes with synovial fluid from RA patients clearly enhanced the effects of IL-4, IL-13 and IL-10. Surprisingly, the effect of synovial fluid was not driven by IL-10 of IL-13, suggesting the presence of another CCL18 inducing factor in synovial fluid. CONCLUSION: In summary, IL-10 synergistically induces CCL18 secretion in combination with IL-4 of IL-13 on monocytes and monocyte derived cells. The effects of IL-14, IL-13 and IL-10 are strongly enhanced by synovial fluid. This synergy may contribute to the high CCL18 expression in RA

Differential role of NK cells against Candida albicans infection in immunocompetent or immunocompromised mice

International audienceLittle is known regarding the role of NK cells during primary and secondary disseminated Candida albicans infection. We assessed the role of NK cells for host defense against candidiasis in immunocompetent, as well as immunodeficient, hosts. Surprisingly, depletion of NK cells in immunocompetent WT mice did not increase susceptibility to systemic candidiasis, suggesting that NK cells are redundant for antifungal defense in otherwise immunocompetent hosts. NK-cell-depleted mice were found to be protected as a consequence of attenuation of systemic inflammation. In contrast, the absence of NK cells in T/B/NK-cell-deficient NSG (NOD SCID gamma) mice led to an increased susceptibility to both primary and secondary systemic C. albicans infections compared with T/B-cell-deficient SCID mice. In conclusion, this study demonstrates that NK cells are an essential and nonredundant component of anti-C. albicans host defense in immunosuppressed hosts with defective T/B-lymphocyte immunity, while contributing to hyperinflammation in immunocompetent hosts. The discovery of the importance of NK cells in hosts with severe defects of adaptive immunity might have important consequences for the design of adjunctive immunotherapeutic approaches in systemic C. albicans infections targeting NK-cell function

Reconstitution of CD161-expressing T cells in patients after allo-SCT.

<p>(A) Percentage of circulating CD161⁺ within CD4⁺ and CD161^hi within CD8⁺ T cells in patients at 1 (<i>n</i> = 11, 20), 3 (<i>n</i> = 50, 71), 6 (<i>n</i> = 19, 24), and 12 (<i>n</i> = 19, 22) months after allo-SCT. (B) Absolute levels of circulating CD161⁺CD4⁺ and CD161^hiCD8⁺ T cells in patients at 1 (<i>n</i> = 8, 20), 3 (<i>n</i> = 50, 71), 6 (<i>n</i> = 19, 24), and 12 (<i>n</i> = 19, 22) months after allo-SCT. (C) Absolute number of circulating CD161⁻CD4⁺ and CD161^neg/lowCD8⁺ T cells in patients at 1 (<i>n</i> = 8, 20), 3 (<i>n</i> = 54, 69), 6 (<i>n</i> = 19, 24), and 12 (<i>n</i> = 19, 22) months after allo-SCT. (D) Correlation between the percentage of circulating CD161⁺CD4⁺ and CD4⁺ T cells (<i>n</i> = 58), and CD161^hiCD8⁺ T cells and CD8⁺ T cells (<i>n</i> = 70) at 3 months after allo-SCT. Lines represent median value, grey areas represent the reference range of healthy controls (mean ± SD). Statistical analysis was performed using a One-way ANOVA followed by a Bonferroni post-hoc test (CD4) or non-parametric One-way ANOVA followed by a Dunns post-hoc test (CD8). Correlations were determined by calculating the Spearman correlation coefficient (R). *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001.</p

Patient characteristics.

<p>Abbreviations: ALL, acute lymphatic leukemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; CML, chronic myeloid leukemia; NHL, non-Hodgkin lymphoma; CLL, chronic lymphatic leukemia; Cy, <b><i>cyclophosphamide; Bus, busulphan; TBI, total body irradiation</i></b>; <b><i>Ida, idarubicin;</i></b> GVHD, graft-versus-host disease.</p

CCL20 is expressed in GVHD tissues and selectively attracts CCR6⁺ T cells.

<p>(A) CCL20 staining in skin biopsies of patients diagnosed with acute GVHD at respectively 49 (UPN 833) and 30 days (UPN 877), or chronic GVHD 127 days (UPN 722) and 321 days (UPN 741) days after allo-SCT. Squares indicate examples of single cells in the dermis in close proximity to the epidermal-dermal junction (acute GVHD) or in the epidermis which are situated in close proximity to or at the epidermal-dermal junction (chronic GVHD). Images were captured at 400X. (B) CD3 (red), CD4 (blue), and CCR6 (green) triple staining in skin biopsies of patients diagnosed with acute GVHD at respectively 49 (UPN 833) and 30 days (UPN 877), or chronic GVHD 127 days (UPN 722) and 321 days (UPN 741) days after allo-SCT. White arrows and squares indicate examples of CD3⁺CD4⁺CCR6⁺ cells, yellow arrows and squares indicate examples of CD3⁺CD4⁻CCR6⁺ cells. Single stainings of the cells in squares are depicted under the image. Images were captured at 400X.</p