scholarly journals IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization

2016 ◽  
Vol 213 (10) ◽  
pp. 2147-2166 ◽  
Author(s):  
Juhan Yoon ◽  
Juan Manuel Leyva-Castillo ◽  
Guoxing Wang ◽  
Claire Galand ◽  
Michiko K. Oyoshi ◽  
...  
Keyword(s):  
T Cells ◽  
Human Skin ◽  
Cd4 T Cells ◽  
Mouse Skin ◽  
Skin Inflammation ◽  
Serum Levels ◽  
Skin Lesions ◽  
Tape Stripping ◽  
Keratinocyte Proliferation ◽  
Th22 Cells

Atopic dermatitis (AD) is a Th2-dominated inflammatory skin disease characterized by epidermal thickening. Serum levels of IL-22, a cytokine known to induce keratinocyte proliferation, are elevated in AD, and Th22 cells infiltrate AD skin lesions. We show that application of antigen to mouse skin subjected to tape stripping, a surrogate for scratching, induces an IL-22 response that drives epidermal hyperplasia and keratinocyte proliferation in a mouse model of skin inflammation that shares many features of AD. DC-derived IL-23 is known to act on CD4+ T cells to induce IL-22 production. However, the mechanisms that drive IL-23 production by skin DCs in response to cutaneous sensitization are not well understood. We demonstrate that IL-23 released by keratinocytes in response to endogenous TLR4 ligands causes skin DCs, which selectively express IL-23R, to up-regulate their endogenous IL-23 production and drive an IL-22 response in naive CD4+ T cells that mediates epidermal thickening. We also show that IL-23 is released in human skin after scratching and polarizes human skin DCs to drive an IL-22 response, supporting the utility of IL-23 and IL-22 blockade in AD.

scholarly journals Type 17 Immune Response Facilitates Progression of Inflammation and Correlates with Cognition in Stable Schizophrenia

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 926
Author(s):  
Milica M. Borovcanin ◽  
Slavica Minic Janicijevic ◽  
Ivan P. Jovanovic ◽  
Nevena M. Gajovic ◽  
Milena M. Jurisevic ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Serum Levels ◽  
Antipsychotic Therapy ◽  
Necrosis Factor Alpha ◽  
Positive Correlation ◽  
Tnf Α ◽  
Immune Pathway

Dysregulation of the type 17 immune pathway has already been considered in schizophrenia and we previously measured decreased sera values of interleukin (IL)-17 in early stages. We further explored the possible correlation of IL-17 systemic levels with proinflammatory cytokines and cognitive scores and additionally analyzed the percentage of IL-17 producing lymphocytes in peripheral blood of patients with stable schizophrenia. We included 27 patients diagnosed with schizophrenia (F20), after a three-month stable depot antipsychotic therapy (risperidone or paliperidone) and 18 healthy control subjects. Positive and Negative Syndrome Scale of Schizophrenia and the Montreal-Cognitive Assessment (MoCA) were conducted. Sera concentrations of IL-17, IL-6, tumor necrosis factor alpha (TNF-α) and soluble ST2 receptor (sST2) were measured. Flow cytometry and Natural Killer (NK) and T cell analyses were done in 10 patients and 10 healthy controls. Moderate positive correlation was established between IL-17 and TNF-α (r = 0.640; p = 0.001), IL-17 and IL-6 (r = 0.514; p = 0.006), IL-17 and sST2 (r = 0.394; p = 0.042). Furthermore, a positive correlation between the serum levels of IL-17 and MoCA scores was observed, especially with visuospatial and executive functioning, as well as language functioning and delayed recall (p < 0.05). Significantly higher percentage of IL-17 producing CD56+ NK cells was measured in peripheral blood of patients with schizophrenia in remission vs. healthy individuals (p = 0.001). The percentage of CD4+ T cells and CD4+ T cells that produce IL-17 was significantly increased in patients (p = 0.001). This study revealed the involvement of innate type 17 immune response in the progression of inflammation and this could be related to cognitive functioning in stable schizophrenia.

scholarly journals Interleukin-17A Drives IL-19 and IL-24 Expression in Skin Stromal Cells Regulating Keratinocyte Proliferation

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaofei Xu ◽  
Errol Prens ◽  
Edwin Florencia ◽  
Pieter Leenen ◽  
Luis Boon ◽  
...  
Keyword(s):  
Human Skin ◽  
Stromal Cells ◽  
Skin Inflammation ◽  
Skin Fibroblasts ◽  
Psoriatic Skin ◽  
Human Skin Fibroblast ◽  
Antibody Treatment ◽  
Keratinocyte Proliferation ◽  
Cellular Source ◽  
Enhanced Expression

IL-17A has been shown to be up-regulated in psoriasis lesions and is central to psoriasis pathogenesis. IL-19, along with other IL-20 subfamily cytokines such as IL-20 and IL-24, is induced by IL-17A and contributes especially to epidermal hyperplasia in psoriasis. However, the regulation, cellular sources of IL-19 and whether targeting of IL-17A by biologics influence IL-19 expression is not completely understood. To investigate the regulation of IL-19 by IL-17A in psoriasis, the imiquimod-induced psoriasis mouse (IMQ) model was used. Enhanced expression of IL-17A in the IMQ model was achieved by anti-IL-10 antibody treatment. Assessments of skin inflammation macroscopically, by histology and flow cytometry, all confirmed increased psoriatic symptoms. Interestingly, depletion of IL-10 markedly upregulated IL-23/IL-17 pathway related cytokines followed by a significant increase in IL-19 and IL-24. The up-regulation of IL-19 and IL-24, but not IL-17A, coincided with increased keratinocyte proliferation. To investigate the cellular source and effects of biologics on IL-19, human skin fibroblasts from healthy controls and psoriasis patients were cultured alone or co-cultured with activated memory CD4+ T cells. Besides IL-1β, IL-17A induced direct expression of IL-19 and IL-24 in skin fibroblasts and keratinocytes. Importantly, intrinsic higher expression of IL-19 in psoriatic skin fibroblasts was observed in comparison to healthy skin fibroblasts. Neutralization of IL-17A in the human skin fibroblast-T cell co-culture system significantly suppressed IL-19 and IL-24 expression. Together, our data show that IL-17A-induced IL-19 and IL-24 expression in skin stromal cells contribute to keratinocyte proliferation.

scholarly journals Decreased expression of Sirt1 contributes to ocular Behcet’s disease progression via Th17 and Th22 response

2020 ◽  
Author(s):  
Manyun Xie ◽  
Yan Yang
Keyword(s):  
T Cells ◽  
Behçet’S Disease ◽  
Cd4 T Cells ◽  
Behcet’S Disease ◽  
Behçet's Disease ◽  
Cell Counting ◽  
Behcet's Disease ◽  
Sirt1 Expression ◽  
Th22 Cells

Background: Previous studies have indicated that Sirtuin 1 (Sirt1) plays an important role in suppressing inflammatory responses in many diseases. However, the Sirt1 levels and role of Sirt1 in ocular Behcet’s disease (OBD) have not been fully elucidated. Objective: To investigate the role of Sirt1 in the pathogenesis of OBD. Methods: Sirt1 and cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA). Cell viability was determined using the Cell Counting Kit-8. The frequencies of Th17 and Th22 cells were detected using flow cytometry. Results: We found decreased expression of Sirt1 in CD4+ T cells obtained from patients with active OBD. SRT1720, an agonist of Sirt1, significantly upregulated Sirt1 expression in CD4+ T cells from patients with active OBD. Sirt1 activation by SRT1720 significantly suppressed the production of interleukin (IL)-17 and IL-22 by CD4+ T cells and inhibited the expansion of Th17 and Th22 cells. Conclusion: Our results suggest that decreased Sirt1 expression might be involved in the pathogenesis of OBD and that activation of Sirt1 might be considered a potential target for OBD.

Elevated Serum sIL-2Ra Levels Facilitate IL-2 Signaling and Contribute to Impaired Tumor Immunity in B-Cell Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 281-281
Author(s):  
Zhi-Zhang Yang ◽  
Steven C. Ziesmer ◽  
Anne J. Novak ◽  
Thomas E. Witzig ◽  
Stephen M. Ansell
Keyword(s):  
T Cells ◽  
Tumor Immunity ◽  
Cd4 T Cells ◽  
Culture Medium ◽  
Interleukin 2 ◽  
Elevated Serum ◽  
Foxp3 Expression ◽  
Serum Levels ◽  
Poor Prognostic Factor ◽  
The Mean

Abstract Abstract 281 Elevated serum levels of soluble interleukin-2 receptor alpha (sIL-2Ra) have been shown to be a poor prognostic factor in various malignancies and sIL-2Ra levels have generally correlated with tumor bulk and advanced stage of disease. In a clinical trial of single agent rituximab in previously untreated follicular lymphoma (FL) patients, we found that sIL-2Ra levels were elevated compared to controls and increased sIL-2Ra levels prior to treatment were associated with a poor outcome. The mean sIL-2Ra level (+/− standard deviation) in untreated FL patients (n=32) was 2.13 ng/ml (+/− 1.81) and 1.09 ng/ml (+/− 1.53) for normal controls (n=16). The time to progression for previously untreated FL patients after 4 doses of rituximab was 12 months for patients with sIL-2Ra levels above the mean compared to 40 months for patients with low sIL-2Ra levels (p=0.003) confirming that elevated sIL-2Ra is a poor prognostic factor in FL. To explore the mechanism by which sIL-2Ra may contribute to a poor prognosis, we determined the source of sIL-2Ra and whether sIL-2Ra facilitates interleukin-2 (IL-2) signaling. Based on our previous work showing that IL-2 induces Foxp3 expression, we particularly evaluated whether sIL-2Ra may bind IL-2 and contribute to impaired anti-tumor immunity by promoting Treg cell development. We found that sIL-2Ra could be detected by ELISA in the culture medium of IL-2Ra-expressing cell lines such as SuDHL1 and Karpas299 and that activation of these cells with PMA/Ionomycin significantly increased sIL-2Ra levels in the culture medium. Production of sIL-2Ra was associated with an attenuation of surface IL-2Ra expression on SuDHL1 and Karpas299 cells suggesting that surface IL-2Ra is the source of sIL-2Ra. Next, using histo-tagged sIL-2R, we tested whether the complex between sIL-2Ra and IL-2 was able to bind to IL-2R on the malignant cell. We found that sIL-2Ra bound IL-2 and that the complex could be detected on the surface of IL-2R-expressing cells. We then compared the signaling of the sIL-2Ra/IL-2 complex to that of IL-2 alone. As expected, we found that IL-2 stimulated cell proliferation, enhanced STAT5 phosphorylation and upregulated Foxp3 expression in CD4+ T cells in a dose-dependent manner. Administration of an anti-IL-2 antibody attenuated these effects. In contrast, sIL-2Ra alone had little effect on cell proliferation, STAT5 phosphorylation and Foxp3 expression. However, the addition of sIL-2Ra to IL-2 prior to incubation with IL-2R-expressing cells enhanced IL-2-mediated phosphorylation of STAT5 and Foxp3 expression in CD4+ T cells. Compared to IL-2 alone, treatment with sIL-2Ra (25ng/ml) and IL-2 (25ng/ml) increases the number of CD4+ T cells with phosphorylation of STAT5 from 7.9% to 17.4%. Taken together, these results indicate that sIL-2R plays an active biologic role in FL by binding IL-2 and promoting IL-2 signaling rather than depleting IL-2 and blocking its function. Given the findings that IL-2 strongly induces Foxp3 expression and promotes Treg cell development and that Treg cells suppress anti-tumor immunity, we conclude that elevated serum levels of sIL-2Ra facilitate IL-2 signaling and thereby contribute to a poor prognosis in FL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immune Enhancement of Skin Carcinogenesis by CD4+ T Cells

2003 ◽  
Vol 197 (8) ◽  
pp. 1017-1028 ◽  
Author(s):  
Dylan Daniel ◽  
Nicole Meyer-Morse ◽  
Emily K. Bergsland ◽  
Kerstin Dehne ◽  
Lisa M. Coussens ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Skin Lesions ◽  
Skin Carcinogenesis ◽  
Neoplastic Progression ◽  
Multi Stage ◽  
Malignant Lesions ◽  
Immune Enhancement ◽  
Metalloproteinase 9 ◽  
Reduced Activity

In a transgenic model of multi-stage squamous carcinogenesis induced by human papillomavirus (HPV) oncogenes, infiltrating CD4+ T cells can be detected in both premalignant and malignant lesions. The lymph nodes that drain sites of epidermal neoplasia contain activated CD4+ T cells predominantly reactive toward Staphylococcal bacterial antigens. HPV16 mice deficient in CD4+ T cells were found to have delayed neoplastic progression and a lower incidence of tumors. This delay in carcinogenesis is marked by decreased infiltration of neutrophils, and reduced activity of matrix metalloproteinase-9, an important cofactor for tumor progression in this model. The data reveal an unexpected capability of CD4 T cells, whereby, proinflammatory CD4+ T cells, apparently responding to bacterial infection of dysplastic skin lesions, can inadvertently enhance neoplastic progression to invasive cancer.

Lactobacillus salivarius LA307 and Lactobacillus rhamnosus LA305 attenuate skin inflammation in mice

2018 ◽  
Vol 9 (2) ◽  
pp. 299-309 ◽  
Author(s):  
S. Holowacz ◽  
C. Blondeau ◽  
I. Guinobert ◽  
A. Guilbot ◽  
S. Hidalgo ◽  
...  
Keyword(s):  
Skin Diseases ◽  
Oral Treatment ◽  
Lactobacillus Rhamnosus ◽  
Skin Inflammation ◽  
Serum Levels ◽  
Skin Lesions ◽  
Lactobacillus Salivarius ◽  
Tnf Α ◽  
Microscopic Evaluation ◽  
Chronic Skin

Oral probiotics potential for the management of dermatological diseases is vast. However, results of available studies in skin diseases, such as atopic dermatitis (AD), are inconsistent, partly because probiotic effects are strain specific. Careful selection of probiotic strains is therefore indispensable to ensure efficacy of treatment. In this study, Lactobacillus salivarius LA307, Lactobacillus rhamnosus LA305 and Bifidobacterium bifidum PI22, three strains that were previously identified for their interesting immunomodulatory properties in allergy and/or colitis models, were assessed in the prevention of chronic skin inflammation induced by repeated applications of 12-O-tetradecanoylphorbol-13-acetate in hairless SKH-1 mice. Macroscopic and microscopic evaluation of skin lesions was performed together with measurements of serum levels of interleukin (IL)-1β, IL-6, tumour necrosis factor alpha (TNF-α), IL-17, IL-22, IL-10 and IL-4. Daily oral treatment with the three strains at the dose of 1×109 cfu/day for 3 weeks limited the development of chronic skin inflammation, the effects being strain dependent. Indeed the two Lactobacillus strains significantly limited the intensity of skin inflammation both at the macroscopic and microscopic levels. Macroscopic observations were correlated to the histological observations and the resulting microscopic score. This limitation of the development of AD-like skin lesions involved the modulation of cytokine production. Treatment with the two Lactobacillus strains induced a decrease in the serum levels of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, IL-17, IL-22 and at the opposite an increase in the production of the anti-inflammatory cytokine IL-10 and also of IL-4. Globally, B. bifidum PI22 had lower benefits. These results obtained in mice suggest that L. salivarius LA307 and L. rhamnosus LA305 could be good candidates for preserving skin integrity and homeostasis via the modulation of the gut microbiota and that their use could be beneficial in dermatological conditions such as AD.

scholarly journals VEGF-Trap decreases CD4+ T cells, Th17 cytokines improving psoriasis-like skin inflammation in KC-Tie2 mice

2013 ◽  
Vol 72 (3) ◽  
pp. 322-325 ◽  
Author(s):  
Doina Diaconu ◽  
Yi Fritz ◽  
Sean M. Dawes ◽  
Candace M. Loyd ◽  
Nicole L. Ward
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Skin Inflammation ◽  
Th17 Cytokines ◽  
Vegf Trap

scholarly journals Characterization of Mycobacterium tuberculosis-specific Th22 cells and the effect of tuberculosis disease and HIV co-infection

2020 ◽  
Author(s):  
Mohau S. Makatsa ◽  
F. Millicent A. Omondi ◽  
Rubina Bunjun ◽  
Robert J. Wilkinson ◽  
Catherine Riou ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Latent Tuberculosis ◽  
Th22 Cells ◽  
Distinct Subset ◽  
Increased Risk ◽  
Ifn Γ

ABSTRACTThe development of a highly effective tuberculosis (TB) vaccine is likely dependent on our understanding of what constitutes a protective immune response to TB. Accumulating evidence suggests that CD4+ T cells producing IL-22, a distinct subset termed ‘Th22’ cells, may contribute to protective immunity to TB. Thus, we characterized Mycobacterium tuberculosis (Mtb)-specific Th22 (and Th1 and Th17) cells in 72 individuals with latent tuberculosis infection (LTBI) or TB disease, with and without human immunodeficiency virus (HIV)-1 infection. We investigated the functional properties (IFN-γ, IL-22 and IL-17 production), memory differentiation (CD45RA, CD27 and CCR7) and activation profile (HLA-DR) of Mtb-specific CD4+ T cells. In HIV-uninfected individuals with LTBI, we detected abundant IFN-γ producing CD4+ T cells (median: 0.93%) and IL-22-producing CD4+ T cells (median: 0.46%) in response to Mtb. The frequency of IL-17 producing CD4+ T cells was much lower, at a median of 0.06%. Consistent with previous studies, IL-22 was produced by a distinct subset of CD4+ T cells and not co-expressed with IL-17. Mtb-specific IL-22 responses were markedly reduced (median: 0.08%) in individuals with TB disease and HIV co-infection compared to IFN-γ responses. Mtb-specific Th22 cells exhibited a distinct memory and activation phenotype compared to Th1 and Th17 cells. Furthermore, Mtb-specific IL-22 was produced by conventional CD4+ T cells that required T cell receptor (TCR) engagement. In conclusion, we confirm that Th22 cells contribute substantially to the immune response to TB. Depletion of Mtb-specific Th22 cells during HIV co-infection may contribute to increased risk of TB disease.

scholarly journals Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

2016 ◽  
Vol 197 (8) ◽  
pp. 3406-3414 ◽  
Author(s):  
Matthias Pink ◽  
Boris A. Ratsch ◽  
Maibritt Mardahl ◽  
Pawel Durek ◽  
Julia K. Polansky ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
Cd4 T Cells ◽  
Skin Inflammation
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