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.
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.