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Event: 1822

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Maturation of TNF/iNOS-Producing Dendritic Cells

Short name

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Maturation, TNF/iNOS-Producing Dendritic Cells

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Skin disease by stimulation of TLR7/8	KeyEvent	Hiroyuki Komatsu (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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⁺CD14^intCD206⁺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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Detection of Tip-DC is considered to be done by:

Flowcytometry
RT-qPCR

^{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

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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).

References

List of the literature that was cited for this KE description. More help

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.