Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Skin disease by stimulation of TLR7/8||KeyEvent|
Key Event Description
A distinct population of human blood DCs that are defined by the selective expression of the 6-sulfo LacNAc residue on the P-selectin glycoprotein ligand 1 membrane molecule was described previously. 6-Sulfo LacNAc DCs (slanDCs) stand out by a marked production of TNF-α, and they were recognized as the major source of IL-12p70 among blood leukocytes when stimulated with CD40 ligand or LPS of gramnegative bacteria (Hänsel et al. 2011).
According to the current concept, these inflammatory DCs are CD1c–, CD11c+ cells locally expressing TNF-α and iNOS. They were also referred to as TNF and inducible nitric oxide synthase–expressing DCs (Tip-DCs) (Lowes et al. 2005) or inflammatory dermal DCs (Zaba et al. 2009). In contrast, resident dermal DCs express CD1c and CD11c and were shown to lack inflammatory markers. The phenotype of slanDCs (CD11c+ and CD1c-) and their local production of IL-23p19, TNF-α, and iNOS identify slanDCs as being a population of inflammatory dermal DCs and so-called Tip-DCs in psoriasis (Hänsel et al. 2011).
Stimulation of blood DCs with self-RNA–LL37 complexes induced a robust TNF-α response (Hänsel et al. 2011). TNF-α affects Tip-DCs in an autocrine and/or paracrine manner (Zaba et al. 2007).
DC activation is known to be enhanced by IFN-α in the presence of TNF-α (Luft et al. 1998).
R848 induces IL-23 production from activated human monocyte-derived DCs (moDCs) by enhanced transcriptional activity (Schwarz et al. 2013).
IL-23 is a heterodimer, sharing a p40 subunit with IL-12 but having a distinct p19 subunit. IL-23 binds to IL-12Rβ1 but not IL-12Rβ2. The receptor for this cytokine is heterodimeric and uses a novel second subunit, IL-23R, which is a member of the hematopoietin receptor family (Lee et al. 2004).
How It Is Measured or Detected
IL-23 in cell-free supernatants collected after R848 stimulation to moDCs is detected by ELISA (Schwarz et al. 2013). Expression of IL-23 mRNA in R848-stimulated moDCs is measured by qRT-PCR (Schwarz et al. 2013).
Domain of Applicability
pDCs were prepared from mouse spleen, and cytokine production after culture with IMQ was measured. IFN-a production from splenic pDCs was induced by IMQ treatment. The production of IL-23, IL-6 and TNF-α was also induced by IMQ treatment. Although 4–8% of mPDCA-1- CD11c+ DCs were contaminated in prepared mPDCA-1+ pDC fraction, we confirmed that splenic mPDCA-1- CD11c+ DCs enriched to approximately 80% purity could not produce IL-23 and TNF-α by IMQ stimulation. In Tlr7-/- splenic pDCs, these cytokines (IFN-α, IL-23, IL-6 and TNF-α) were not induced by IMQ treatment, although stimulation by CpG, a TLR9 ligand, resulted in induction of these cytokines at the same level as was produced by wild-type splenic pDCs. These data indicate that, in mice, IMQ application can induce the production via TLR7 of IFN-a, IL-23, IL-6 and TNF-α from pDCs existing in the skin in vivo (Ueyama et al. 2014).
- Hänsel, A., Günther, C., Ingwersen, J., Starke, J., Schmitz, M., Bechmann, M., Meurer, M., Rieber, E.P. and Schäkel, K. (2011). Human slan (6-sulfoLacNAc) dendritic cells are inflammatory dermal dendritic cells in psoriasis and drive strong TH17/TH1 T-cell responses. Journal of allergy and clinical immunology 127(3), 787-794.
- Lee, E., Trepicchio, W.L., Oestreicher, J.L., Pittman, D., Wang, F., Chamian, F., Dhodapkar, M. and Krueger, J.G. (2004). Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. Journal of experimental medicine 199(1), 125-130.
- Lowes, M.A., Chamian, F., Abello, M.V., Fuentes-Duculan, J., Lin, S.L., Nussbaum, R., Novitskaya, I., Carbonaro, H., Cardinale, I., Kikuchi, T., Gilleaudeau, P., Sullivan-Whalen, M., Wittkowski, K.M., Papp, K., Garovoy, M., Dummer, W., Steinman, R.M. and Krueger, J.G. (2005). Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proceedings of the national academy of sciences of the United States of America 102(52), 19057-19062.
- Luft, T., Pang, K.C. Thomas, E., Hertzog, P., Hart, D.N., Trapani, J. and Cebon, J. (1998). Type I IFNs enhance the terminal differentiation of dendritic cells. Journal of immunology 161(4), 1947-1953.
- Schwarz, H., Posselt, G., Wurm, P., Ulbing, M., Duschl, A. and Horejs-Hoeck, J. (2013). TLR8 and NOD signaling synergistically induce the production of IL-1β and IL-23 in monocyte-derived DCs and enhance the expression of the feedback inhibitor SOCS2. Immunobiology 218(4), 533-42.
- Ueyama, A., Yamamoto, M., Tsujii, K., Furue, Y., Imura, C., Shichijo, M. and Yasui, K. (2014). Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: a role for interferon-alpha in dendritic cell activation by imiquimod. Journal of dermatology 41(2), 135-143.
- Zaba, L.C., Cardinale, I., Gilleaudeau, P., Sullivan-Whalen, M., Suárez-Fariñas, M., Fuentes-Duculan, J., Novitskaya, I., Khatcherian, A., Bluth, M.J., Lowes, M.A. and Krueger, J.G. (2007). Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. Journal of experimental medicine 204(13), 3183-3194.
- Zaba, L.C., Krueger, J.G. and Lowes, M.A. (2009). Resident and “inflammatory” dendritic cells in human skin. Journal of investigative dermatology 129(2), 302-308.