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. 2017 Apr 5;8:294. doi: 10.3389/fimmu.2017.00294

Figure 5.

Figure 5

Interactions between type I interferons (T1-IFNs) and Th17 immunity in autoimmune diseases. The color grading in the figure indicates the level of involvement of either Th17 immunity or T1-IFN-associated signaling. (1) T1-IFNs, primarily produced by plasmacytoid dendritic (pDC) but also by inflammatory dendritic cells (iDC) and PMN, prime the latter cells toward a T1-IFN/B-cell activating factor (BAFF)-producing phenotype, promote NETosis by PMN and stimulate monocyte migration by inducing CCL2 production. (2) BAFF activates B-cells, stimulates tertiary lymphoid structures (TLS) formation together with CXCL13, directly promotes Th17 differentiation (not shown), and stimulates the release of IL-1β by iDC. (3) TLS facilitate optimal interaction between activated B-cells and antigen-presenting cells (APC), while necrosis, neutrophil extracellular traps, and T1-IFN increase the chance that these APC present self-antigens. Subsequent germinal center (GC) reactions within these TLS result in B-cells differentiating into plasma cells that produce large quantities of autoantibodies. These autoantibodies can mediate tissue damage and sustain a self-amplifying loop by inducing NETosis through binding the Fc-receptor on PMN. B-cells can also contribute to Th17 immunity by their ability to secrete IL-6 and GM-CSF (not shown and uncertain if this is BAFF dependent). (4) NETs trap antibodies. This facilitates their Fc-receptor-mediated internalization by pDC in which they stimulate T1-IFN production through endosomal TLR9 activation. Circulating NETs also stimulate IL-1β production by iDC and can mediate tissue damage. (5) In a pro-inflammatory feedback loop, IL-23 stimulates the development of GM-CSF-producing Th17 cells (Th17.1), which in turn, together with BAFF and/or NETs stimulate an inflammatory phenotype in iDC. (6) IL-1β and IL-23 stimulate IL-17 production by γδ T-cells, while concomitant stimulation with IL-1β and TNF-α is required for IL-17-induced G-CSF and chemokine production in parenchymal cells. (7) IL-1β and TNF-α activate PMN to release reactive oxygen species (ROS) and proteases that cause tissue damage. Furthermore, GM-CSF increases longevity of PMN (not shown). Finally, the priming of PMN and monocytes prior to entering the site of disease is important for their eventual effector function. For monocytes this is shown in more detail in Figure 3.