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Key Event Title
Th17 cell migration and inflammation induction
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|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 Do not cite||Under Development|
|TLR9 activation leading to Multi Organ Failure and ARDS||KeyEvent||Gillina Bezemer (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
Psoriasis is known to play a major role in the etiology of T cell dysfunction, especially in over activation of the Th17 pathway, which Th17 cells were associated with Th1 and Th2 (Lisa C. et al. 2007) Th17 cell was identified as a cell population that produces different IL17. Abnormal activation of Toll-like receptors (TLR7, 8 and 9) is also involved in the initiation and maintenance of psoriasis. IMO-3100 (an antagonist of TLR7 and 9) and IMO-8400 (an antagonist of TLR7, 8 and 9) has been shown to reduce psoriasis-like skin lesions induced by intradermal administration of IL-23 on the back of mice (Mayte S-F et al. 2013). Immune cell infiltration in psoriasis lesions is composed of CD3 + Th1cell, Th17 cells and CD11c + dendritic cells (DC) (Chamian F et al 2005).
Cytokines such as TNF-α, IFN-γ, IL-17, IL-22, IL-23, IL-12, and IL-1β produced from these cells cause an inflammatory cascade. In particular, the IL-23 / Th17 axis plays an important role, and IL-23h is produce in DC, promotes the differentiation of naive CD4 + T cell progenitor cells into the Th17 phenotype, and stimulates the survival and expansion of the Th17 population (Harrington LE et al. 2005) (Veldhoen M et al. 2006). IL-17 produced from Th17 cells regulates the expression of defensin, S100 family protein and LL-37. These are innate immune responses in the skin and show higher expression of IL-23 in keratinocytes and dermal tissues of psoriatic lesions than in non-lesions (Liang SC et al. 2006).
Overproduction of Th1 and TH17 cytokines is a major cause of psoriasis, and glucocorticoid (GC) regulates epidermal differentiation and acts as a potent anti-inflammatory compound to suppress the pathology of psoriasis. Synthetic glucocorticoids are uses to suppress inflammatory disease including psoriasis, and induce the glucocorticoid-induced leucine zipper (GILZ), a protein that inhibits major immune cell signaling pathways. CILZ is deficient in lesioned skin of psoriasis patients and shows a negative correlation with the expression of pro-inflammatory cytokines IL-1, IL-23, IL-22, and STAT3. Lisa et al. was identified a T cell-specific role of CILZ that limits Th17 cell formation in vitro in response to the Th17-promoting cytokines IL-1β and IL-23 (Lisa M et al.2019). CILZ has the clinical significance of psoriasis as well as the non-redundant function of controlling pathogenic Th17 responses (Lisa M et al.2019).
One of the causes of psoriasis is an increase in pathogenic Th17 cells in people with a genetic predisposition stimulated by the production of Th17 polarized cytokines by bone marrow cells. The antibacterial peptide LL37, which forms a complex with nucleic acids released from cells, is an autoantigen that promotes the activation of cutaneous plasmacytoid dendritic cells and myeloid DCs, and Th17 cells are effector cytokines such as IL-17A. It activates keratinocytes directly through release. Activated keratinocytes proliferate abnormally and release inflammatory mediators and chemokines to amplify the inflammatory response (Boehncke WH et al.2015).
How It Is Measured or Detected
IL17 + cell count measurement
Flow cytometric analysis of psoriasis skin biopsy showed increased IL-17 + and IL-22 + CD4 + T cells,
Measurement of IL17 protein levels (in skin and serum)
Increased frequency of IL-17 +, CCR6 +, and CCR4 + T cells. IL-22-producing cells (Th-22 cells) that do not produce IL-17 or IFNγ also increased (Benham et al. 2013).
Domain of Applicability
Ras homolog gene family H (RhoH) is a membrane-bound adapter protein involved in proximal T cell receptor signaling, and spontaneously develops chronic dermatitis that closely resembles human psoriasis in RhoH gene-deficient mice. Ubiquitin protein ligase E3 component N recognition 5 (Ubr5) and nuclear receptor subfamily 2 group F member 6 (Nr2f6) expression levels are decreased at the lesion site, and protein levels and DNA binding activity of retinoic acid-related orphan receptors are increased is doing. As a result, T cells differentiated into Th17 cells due to increased production of IL-17 and IL-22. These results indicate that RhoH suppresses the differentiation of naive T cells into effector Th17 cells. RhoH is a gene expressed in blood cells, and when RhoH expression decreases in T cells, Th17 cells increase, IL-22 is produced in large quantities, and the epidermis thickens, leading to the formation of psoriasis pathology. Humans with low RhoH expression may become more severe if they suffer from psoriasis.（Journal of Allergy and Clinical Immunology）
The effect of the unique gut flora in psoriasis on the development and reactivity of inflammatory cells on the IL-23 / Th17 axis was analyzed in imiquimod-induced psoriasis model mice. Th17, γδ TCR-bearing lymphocytes in the spleen were measured from sterile (GF) mice, broad-spectrum antibiotic mixture-administered (ATB) mice, and conventional (CV) mice. GF mice and ATB-treated mice had fewer Th17 cells and γδTCR + cells than CV mice. This is thought to be due to the symbiotic bacteria that lack microbiota or changes due to ATB treatment reduce pro-inflammatory T cell response and regulate T cell development. In other words, it is proof that the interaction between the microorganisms of Clostridiales and Elysiperotricales and the host affects the reactivity of Th17 cells and is involved in the etiology of imiquimod-induced skin inflammation. The positive effect of antibiotic regulation of the gut flora on skin severity suggests the involvement of the gut and skin axes and is part of the management of psoriasis patients. (Zizana Z et al. 2016) * Wide-area antibiotic mixture (ATB): A mixture of metronidazole, colistin, streptomycin, and vancomycin.
・Lisa C. Zaba, Irma Cardinale, Patricia Gilleaudeau, Mary Sullivan-Whalen, Mayte Suárez-Fariñas, Judilyn Fuentes-Duculan, Inna Novitskaya, Artemis Khatcherian, Mark J. Bluth, Michelle A. Lowes, James G. Krueger. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J. Exp. Med. 2007, 204, 3183-3194.
・Mayte Suarez-Farinas, Robert Arbert, Weiwen Jiang, Francesca S. Ortenzio, Tim Sullivan, James G, Krueger.Suppression of Molecular Inflammatory Pathways by Toll-Like Receptor7,8 and 9 Antagonists in a Model of IL-23-Induced Skin Inflammmation. PLOS ONE, December 2013/Vol 8/Issue 12/e84634
・Chamian F, Lowes MA, Lin SL, Lee E, Kikuchi T et al. (2005)Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci U S A 102: 2075-2080.
・Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL et al. (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123-1132.
・Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B(2006) novo differentiation of IL-17-producing T cells. Immunity 24:179-189.
・Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K et al. (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203:2271-2279.
・Lisa M. Paloma Perez. Glucocorticoids and Glucocorticoid-Induced-Leucine-Zipper (GILZ) in Psoriasis:Published online 2019 Sep 13.
・Boehncke WH, Schon MP. Psoriasis. Lancet (2015)386(9997);983-94.10.1016/S0140-6736(14)61909-7
・Helen Benham, Jane C Goodall, Mihir D Wechalekar, and Dliver Fitzgerald. Th17 and Th22 cells in psoriatic arthritis and psoriasis. Arthritis research & therapy September 2013.
・Journal of Allergy and Clinical Immunology
・Zuzana Zakostelska, Jana Malkova, Kiara Klimesova, Pavel Rossmann, Michaela Hornova, Iva Novosadova, Zuzana Stehlikova, Martin Kostovcik, Tomas Hudcovic, Ranata Stepankova, Katerina Juzlova, Jana Hercogova, Helena Tlaskalova-Hogenova, Miloslav Kverka. Intestinal MicrobiotaPromotes Psoriasis-Like Skin Inflammation by Enhancing Th17 Response. PLOS ONE. 2016;Jul 19.