SEARCH

SEARCH BY CITATION

To the Editor:

Type I interferons (IFNs) play a critical role in the pathogenesis of several autoimmune rheumatic diseases and inflammatory conditions (1–4). We read with interest the recent report by Bilgic et al, who evaluated the capacity of type I IFN–dependent peripheral blood gene and chemokine signatures and levels of proinflammatory cytokines to serve as biomarkers for disease activity in adult and juvenile dermatomyositis (DM) (4). The authors found that prominent type I IFN signatures, such as serum interleukin-6 (IL-6) levels and IFN-driven chemokine levels, correlated strongly with DM disease activity (4). We conducted a study to explore how innate immune cells, and in particular myeloid dendritic cells (DCs), contribute to type I IFN–induced elevations in levels of inflammatory cytokines and chemokines. DCs secrete a wide range of inflammatory mediators that are critically involved in the pathogenesis of autoimmune diseases including DM (5).

DCs were generated by culturing monocytes for 6 days in the presence of granulocyte–macrophage colony-stimulating factor (GM-CSF) and IL-4 (conventional DCs) or a combination of GM-CSF, IL-4, and type I IFN (IFN-DCs). As shown in Figure 1A, type I IFN significantly enhanced the secretion of the inflammatory cytokines IL-8, IL-6, and IL-1β, and moderately enhanced the secretion of tumor necrosis factor α, by DCs. The results thus indicate that DCs are the possible cellular source of the enhanced IL-6 levels observed in patients with DM. Further, we found that type I IFN significantly enhanced secretion of CCL19 (macrophage inflammatory protein 3β), an IFN-inducible chemokine that has many inflammatory properties, by DCs (Figure 1B). Ectopic expression of CCL19 can retain mature and activated DCs in target tissue and can mediate the influx of CCR7-expressing T cells, macrophages, and B cells, culminating in inflammation-mediated tissue damage and formation of extrafollicular germinal center–like structures at the site of chronic inflammation. However, type I IFN did not modulate the secretion of CCL3 (MIP-1α) or CCL4 (MIP-1β), suggesting that myeloid DCs do not contribute to secretion of the latter type I IFN–induced chemokines.

thumbnail image

Figure 1. Secretion of cytokines and chemokines by human myeloid dendritic cells (DCs) upon stimulation with type I interferon (IFN). Monocytes from peripheral blood mononuclear cells of healthy donors were isolated using CD14 beads (Miltenyi Biotech). CD14+ monocytes were differentiated for 6 days in the presence of granulocyte–macrophage colony-stimulating factor (GM-CSF; 1,000 IU/106 cells) and interleukin-4 (IL-4; 500 IU/106 cells) (open bars) or a combination of GM-CSF, IL-4, and type I IFN (IFN-β1a; 1.5 ng/106 cells) (shaded bars) (all from ImmunoTools). A, Levels of inflammatory cytokines in cell-free culture supernatants of DCs differentiated for 6 days, as analyzed by cytometric bead array assay (BD Biosciences). B, Levels of chemokines in cell-free culture supernatants of DCs differentiated for 6 days, as analyzed by enzyme-linked immunosorbent assay (R&D Systems). Data are presented as box plots, where the boxes represent the 25th to 75th percentiles, the lines within the boxes represent the median, and the lines outside the boxes represent the minimum and maximum values. Results are from 4–5 donors. ∗ = P < 0.05 versus cultures without type I IFN, by Mann-Whitney test.

Download figure to PowerPoint

Interestingly, type I IFN significantly down-regulated the secretion of CCL17 and CCL22, the chemokines that recruit Treg cells via CCR4, by DCs (Figure 1B). Treg cells are suppressor cells and play a critical role in down-modulating the inflammatory process by inhibiting the functions of innate cells and effector T cells (6, 7). Our findings thus suggest that by reducing DC secretion of CCL17 and CCL22 and thus limiting Treg cell recruitment, type I IFN enhances inflammation, leading to unabated activation and function of both innate cells and T cells. Taken together, our results indicate that myeloid DCs are one of the major sources of cells involved in type I IFN induction of cytokines and chemokines in DM and other autoimmune rheumatic diseases. In addition, DCs may contribute to inflammation by modulating the recruitment of other immune cells to the site of inflammation.

Acknowledgements

Supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie, Université Paris Descartes, and Agence Nationale de la Recherche (ANR-07-JCJC-0100-01), France.

  • 1
    Hall JC, Rosen A. Type I interferons: crucial participants in disease amplification in autoimmunity. Nat Rev Rheumatol 2010; 6: 409.
  • 2
    Ronnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum 2006; 54: 40820.
  • 3
    Eloranta ML, Lovgren T, Finke D, Mathsson L, Ronnelid J, Kastner B, et al. Regulation of the interferon-α production induced by RNA-containing immune complexes in plasmacytoid dendritic cells [review]. Arthritis Rheum 2009; 60: 241827.
  • 4
    Bilgic H, Ytterberg SR, Amin S, McNallan KT, Wilson JC, Koeuth T, et al. Interleukin-6 and type I interferon–regulated genes and chemokines mark disease activity in dermatomyositis. Arthritis Rheum 2009; 60: 343646.
  • 5
    Khan S, Greenberg JD, Bhardwaj N. Dendritic cells as targets for therapy in rheumatoid arthritis. Nat Rev Rheumatol 2009; 5: 56671.
  • 6
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133: 77587.
  • 7
    Andre S, Tough DF, Lacroix-Desmazes S, Kaveri SV, Bayry J. Surveillance of antigen-presenting cells by CD4+ CD25+ regulatory T cells in autoimmunity: immunopathogenesis and therapeutic implications. Am J Pathol 2009; 174: 157587.

Mohan S. Maddur DVM*, Janakiraman Vani MSc*, Sébastien Lacroix-Desmazes PhD*, Srini V. Kaveri DVM, PhD*, Jagadeesh Bayry DVM, PhD*, * Institut National de la Santé et de la Recherche Médicale Centre de Recherche des Cordeliers Université Pierre et Marie Curie and Université Paris Descartes, Paris, France.