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Key Event Title
Maturation of TNF/iNOS-Producing Dendritic Cells
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
Monocytes are formed in the bone marrow and continuously enter the blood circulation, where they constitute 10% of the total leukocyte population in humans (Sprangers et al. 2016). They are recruited to inflammatory sites and differentiate into immature dendritic cells in situ (Tang-Huau and Segura. 2019). These immature dendritic cells, known as monocyte-derived dendritic cells (mo-DC) are distinguished from conventional or classical DCs which arise from a common DC precursor (Guilliams et al. 2014). They possess typical DC functions of antigen-presenting cells, including the ability to efficiently stimulate naive T cells and the capacity to express CCR7, and potentially enabling their migration to lymph nodes (Tang-Huau and Segura. 2019).
Mo-DC are HLA-DR+CD11c+CD14intCD206+CD1c+ cells. By contrast, they lack the macrophage markers CD16 and CD163. They also display a typical DC morphology: they are small size, possess dendrites and lack large cytoplasmic vacuoles (Tang-Huau and Segura. 2019). Human mo-DC are present in lungs, intestine and peritoneum in the steady-state. Peritoneal mo-DC secrete IL-6, TNF-α, IL-1β and IL-12p70 upon ex vivo re-stimulation. Mo-DC from bronchoalveolar lavage also secrete TNF-α upon re-stimulation (Tang-Huau and Segura. 2019).
Pathogen-derived components, such as Toll-like receptor ligands as well as inflammatory mediators induce maturation of mo-DC. These stimulants include LPS, ssRNA, IFN-α, TNF-α, IFN-γ or CD40L (León et al. 2005, Farkas and Kemény. 2011). TNF-α and inducible nitric oxide synthase (iNOS)-producing DCs (Tip-DCs) are abundant in inflamed tissue such as skin in patients of chronic inflammatory skin disease, and not present in the steady-state or normal skin tissue. These cells are derived from monocyte infiltrated during inflammation and contribute to innate immune response to pathogens including bacteria and parasites (Guilliams et al. 2014).
From the above, monocyte is considered to infiltrate into inflammatory site and differentiate to mo-DC and Tip-DC, sequentially in chronically inflamed tissue. This maturation process is induced and/or promoted by IFN-α, TNF-α and GM-CSF (Farkas and Kemény. 2011).
Tip-DCs express HLA-DR, CD40, CD86, as well as maturation markers DC-Lamp and CD83 but lack the CD207/Langerin and CD14 markers of Langerhans cells and monocytes. In addition, Tip-DCs found in psoriasis produce the inflammatory mediators IL-8, IL-1, STAT1, CCL 20, IL-20, IL-23p19, and IL-12/IL-23p40, which mediate Th1 and Th17 responses (Wilsmann-Theis et al. 2013).
How It Is Measured or Detected
Detection of Tip-DC is considered to be done by:
Analysis of maturation marker expression on cell surface
Maturation markers such as CD80, CD86, CD40 and CD83 can be analyzed by flowcytometry (Wilsmann-Theis et al. 2013).
Quantification of mRNA expression of TNF-α and iNOS
Expression of TNF-α, iNOS, IL-12p35 and IL-23p19 mRNA in in vitro generated Tip-DC are quantified by RT-qPCR. (Wilsmann-Theis et al. 2013).
Domain of Applicability
Tip-DCs are also observed in mice. Murine Tip-DCs are defined as splenic CD11c+, CD11b+, MHC-II+, CD40+, and CD86+ cells producing iNOS and TNF. CD11b expression is observed in murine Tip-DC, however it is lacking on human cells (Lowes et al. 2005).
- Farkas, A. and Kemény, L. (2011). Interferon-α in the generation of monocyte-derived dendritic cells: recent advances and implications for dermatology. British journal of dermatology 165(2), 247-254.
- Guilliams, M., Ginhoux, F., Jakubzick, C., Naik, S.H., Onai, N., Schraml, B.U., Segura, E., Tussiwand, R. and Yona, S. (2014). Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nature review immunology 14(8), 571-578.
- León, B., López-Bravo, M. and Ardavín, C. (2005). Monocyte-derived dendritic cells. Seminars in immunology 17(4), 314-318.
- 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.
- Sprangers, S., Vries, T.J. and Everts, V. (2016). Monocyte Heterogeneity: Consequences for monocyte-derived immune cells. Journal of immunology research 1475435.
- Tang-Huau, T., Segura, E. (2019). Human in vivo-differentiated monocyte-derived dendritic cells. Seminars in Cell & Developmental Biology 86, 44-49.
- Wilsmann-Theis, D., Koch, S., Mindnich, C., Bonness, S., Schnautz, D., von Bubnoff, D. and Bieber, D. (2013). Generation and functional analysis of human TNF-α/iNOS-producing dendritic cells (Tip-DC). Allergy 68(7), 890-898.