Cells In Skin Lesions Research Articles

Immunomodulatory effects of sleep deprivation at different timing of psoriasiform process on skin inflammation

Sleep deprivation affects the pathophysiology of immune-inflammatory skin diseases such as psoriasis. Increasing efforts are directed toward exploring potential mechanisms involving sleep deprivation and immune responses. However, studies focusing on the effects of different timing of sleep deprivation on skin inflammation are lacking. This study thus investigated the immunomodulatory effects of paradoxical sleep (PS) deprivation at different timing of psoriasiform process on skin inflammation in the psoriasis-like mouse model. Male adult C57BL/6 mice were divided into 5 groups (each n = 5): control group (CON), IMQ-S2 group [treating with 31.25 mg imiquimod (IMQ) per day for 5 days with 48 h of PS deprivation on the fourth and fifth day], S2-IMQ group (treating with 31.25 mg IMQ per day for 5 days with 48 h of PS deprivation on the first and second day), 31.25 group (treating with 31.25 mg IMQ per day for 5 days) and 62.5 group (treating with 62.5 mg IMQ per day for 5 days). Compared with IMQ-S2 group and 31.25 group, S2-IMQ group mice had significant increase of IL-17A mRNA level in skin lesions and lymph nodes, and more severe cutaneous inflammation. However, IMQ-S2 group had the highest IL-1β mRNA level in skin lesions and the highest IL-6 mRNA level in lymph nodes among the three groups. Results of flow cytometry showed that frequencies of γδT cell, IL-17A+γδT cell, dendritic cell (DC) and MHCⅡ+ DC in lymph nodes of S2-IMQ group were significantly higher than IMQ-S2 group and 31.25 group, so was the frequency of γδT cells in skin lesions. However, the frequency of DCs in skin lesions of S2-IMQ group was significantly lower than IMQ-S2 group. These data suggest that PS deprivation at the early stage rather than the late stage of psoriasiform process exacerbates the skin inflammation through modulation of the immune system, which may involve that IL-1β and IL-6 stimulated by PS deprivation in turn increasing IL-17 expression through activation and proliferation of γδT cells and DCs migration.

Involvement of Periostin in Skin Function and the Pathogenesis of Skin Diseases.

Skin is a large organ that is susceptible to damage by external forces, chronic inflammation, and autoimmune reactions. In general, tissue damage causes alterations in both the configuration and type of cells in lesional skin. This phenomenon, called tissue remodeling, is a universal biological response elicited by programmed cell death, inflammation, immune disorders, and tumorigenic, tumor proliferative, and cytoreductive activity. During this process, changes in the components that comprise the extracellular matrix are required to provide an environment that facilitates tissue remodeling. Among these extracellular matrix components, periostin (a glycoprotein secreted predominantly by dermal fibroblasts) has attracted much attention. In normal skin, periostin localizes mainly in the papillary dermis and basement membrane of the epidermis. However, it is expressed at higher levels in the dermis of lesional skin of those with atopic dermatitis, scars, systemic/limited scleroderma, melanoma, and cutaneous T cell lymphoma; expression is also increased by damage caused by allergic/autoimmune responses. Furthermore, periostin induces processes that result in development of dermal fibrosis; it also activates or protracts the immune response. The aim of this review is to summarize recent knowledge about the role of periostin in the pathogenesis of dermatoses.

013 - Antibiotics inhibit tumor and disease activity in cutaneous T cell lymphoma

It has been proposed that CD4 T-cell responses to Staphylococcus aureus (SA) can inadvertently enhance neoplastic progression in models of skin cancer and cutaneous T-cell lymphoma (CTCL). In this prospective study, we explored the effect of transient antibiotic treatment on tumor cells and disease activity in 8 patients with advanced-stage CTCL. All patients experienced significant decrease in clinical symptoms in response to aggressive, transient antibiotic treatment. In some patients, clinical improvements lasted for more than 8 months. In 6 of 8 patients, a malignant T-cell clone could be identified in lesional skin, and a significant decrease in the fraction of malignant T cells was observed following antibiotics but an otherwise unchanged treatment regimen. Immunohistochemistry, global messenger RNA expression, and cell-signaling pathway analysis indicated that transient aggressive antibiotic therapy was associated with decreased expression of interleukin-2 high-affinity receptors (CD25), STAT3 signaling, and cell proliferation in lesional skin. In conclusion, this study provides novel evidence suggesting that aggressive antibiotic treatment inhibits malignant T cells in lesional skin. Thus, we provide a novel rationale for treatment of SA in advanced CTCL.

The expression of Th17/Treg cells in skin lesions during leprosy, and its clinical significance

The expression of Th17/Treg cells in skin lesions during leprosy, and its clinical significance

Effect of methotrexate monotherapy on T‐cell subsets in the peripheral circulation in psoriasis

Psoriasis is a T-helper (Th)1/Th17-mediated chronic inflammatory disease. There is an increased population of Th cells in skin lesions and peripheral circulation of patients with psoriasis. Systemic methotrexate (MTX) is an effective treatment for moderate to severe psoriasis; however, its effect on different T-cell subsets is not yet clear. To study the effect of MTX monotherapy on the psoriatic T-cell profile in the peripheral circulation of patients with psoriasis. This was a follow-up study involving 50 patients with moderate to severe psoriasis treated with systemic MTX for 12 weeks. Blood samples (5 mL) were collected from participants, from which PBMCs were isolated, and T-cell phenotyping was performed by flow cytometry. Following 12 weeks of MTX treatment, there was an increase in the percentages of Th2/Treg cells, and a relative decrease in the percentages of Th1/Th17 cells, along with a significant reduction in the median Psoriasis Area and Severity Index (PASI). MTX helps in the restoration of the immune balance by decreasing the numbers of Th1 and Th17 cells and increasing the numbers of Th2 and Treg cells, thus resulting in a significant reduction in disease severity. MTX converts a proinflammatory T-cell phenotype to a protective anti-inflammatory phenotype, thus significantly suppressing the inflammation in psoriasis.

Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature.

Hidradenitis suppurativa (HS) is a chronic skin disease of the pilo-sebaceous apocrine unit characterized by significant inflammation and an impaired quality of life. The pathogenesis of HS remains unclear. To determine the HS skin and blood transcriptomes and HS blood proteome, patient data from previously published studies were analysed and integrated from a cohort of patients with moderate to severe HS (n = 17) compared to healthy volunteers (n = 10). The analysis utilized empirical Bayes methods to determine differentially expressed genes (DEGs) (fold change (FCH) >2.0 and false discovery rate (FDR) <0.05), and differentially expressed proteins (DEPs) (FCH>1.5, FDR<0.05). In the HS skin transcriptome (lesional skin compared to non-lesional skin), there was an abundance of immunoglobulins, antimicrobial peptides, and an interferon signature. Gene-sets related to Notch signalling and Interferon pathways were differentially activated in lesional compared to non-lesional skin. CIBERSORT analysis of the HS skin transcriptome revealed a significantly increased proportion of plasma cells in lesional skin. In the HS skin and blood transcriptomes and HS blood proteome, gene-sets related to the complement system changed significantly (FDR<0.05), with dysregulation of complement-specific DEGs and DEPs. These data point towards an exaggerated immune response in lesional skin that may be responding to commensal cutaneous bacterial presence and raise the possibility that this may be an important driver of HS disease progression.

Single-cell variability drives phenotypic heterogeneity and intrinsic drug-resistance in cutaneous T-cell lymphoma

Aims: Phenotypic heterogeneity allows individual cells to behave different from the bulk. This non-genetic variability provides a critical route to therapeutic resistance and relapse of cancer. Herein, we characterize phenotypic dynamics that generate an intrinsic and pre-existent, drug-tolerant state and identify a resistance biomarker profile to detect these ‘persister’ cells in skin lesions of CTCL.

Effects of extracts of Semen Coicis on a BALB/c mouse model of atopic dermatitis and its mechanism

Objective To evaluate the effects of extracts of Semen Coicis (ESC) on a BALB/c mouse model of atopic dermatitis (AD) , and to explore its potential mechanism. Methods Forty specific pathogen-free (SPF) female BABL/c mice were randomly divided into blank group (8 mice, receiving no treatment) and AD model group (32 mice) . The mice in the model group were topically treated with 2,4-dinitrochlorobenzene (DNCB) in acetone/olive oil to establish the mouse model of AD. After modeling, 8 mice in the blank group and 8 in the model group were sacrificed immediately. The other 24 mice in the model group were randomly and equally divided into 3 groups: model control group receiving no treatment, ESC group and ESC vehicle group topically treated with ESC and ESC vehicle respectively once every day on the back and aural region of the mice for 28 consecutive days. Changes in skin lesions were observed by naked eyes every day. A thickness tester was used to measure the thickness of skin lesions on the left ear before modeling, at completion of modeling and 12 hours after the final treatment. At 12 hours after the final treatment, the mice in the above 3 groups were sacrificed, and the eyeballs were removed for collecting blood. Then, the sera were isolated, and skin tissue specimens were obtained from the skin lesions on the back. These tissue sections were subjected to hematoxylin and eosin (HE) staining and toluidine blue staining for observing the infiltration of inflammatory cells in skin lesions. An immunohistochemical study was performed to determine the expression of aquaporin 3 (AQP3) , Toll-like receptor 2 (TLR2) and TLR4, and enzyme-linked immunosorbent assay (ELISA) to detect the serum levels of IgE, interleukin-4 (IL-4) and interferon-γ (IFN-γ) . Results After 28-day treatment, skin lesions were improved in the ESC group. Compared with the model control group, the ESC group showed a significantly lower clinical symptom score (1.50 ± 0.58 vs. 2.50 ± 0.58, P < 0.05) , decreased lesional thickness on the left ear ([0.31 ± 0.01] mm vs. [0.33 ± 0.01] mm, P < 0.05) , and lower number of infiltrating mast cells per high-power field (15.18 ± 1.64 vs. 28.94 ± 1.28, P < 0.05) . Immunohistochemical findings indicated that the ESC group showed significantly lower expression of AQP3, TLR2 and TLR4 compared with the model control group, and decreased AQP3 expression in the spinous layer. Compared with the model control group, the ESC group showed significantly lower total serum IgE and IL-4 levels, but higher IFN-γ levels (all P < 0.05) . Conclusion Topical ESC is effective for the treatment of skin lesions in mouse models of AD, likely by regulating serum levels of IgE, IL-4 and IFN-γ and affecting the expression of AQP3, TLR2 and TLR4. Key words: Dermatitis, atopic; Semen Coicis; Disease models, animal; Interleukin-4; Interferon-gamma; Toll-like receptors; Aquaporin 3

Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I-driven CD8+ T cell response.

Psoriasis is a complex inflammatory skin disease affecting ∼3% of the population worldwide. Although type I interferons (IFN-I) are thought to be involved in its pathogenesis, the details of this relationship remain elusive. Here we show that in a murine model of imiquimod-driven psoriatic skin inflammation, Foxp3+ regulatory T cells (T reg cells) control inflammation severity by restraining IFN-I. Depletion of T reg cells induces IFN-I and IFN-stimulated gene expression, and leads to accumulation of CD8+ T cells in lesional skin. Mononuclear phagocytes (MNPs) were the source of IFN-I, and their depletion reversed the effect of T reg cell depletion. Blockade of IFN-I signaling abolished CD8+ T cell infiltration and excess inflammation in the skin of T reg cell-depleted mice. Depletion of CD8+ T cells attenuated pathology, confirming their role as critical effector cells downstream of IFN-I. Our results describe an unexpected role for T reg cells in restraint of an MNP-IFN-I-driven CD8+ T cell response during psoriasiform skin inflammation. These findings highlight a pathway with potential relevance for the treatment of early-stage disease.

Phenotype, Function, and Mobilization of 6-Sulfo LacNAc-Expressing Monocytes in Atopic Dermatitis.

Mononuclear phagocytes (MPs) are important immune regulatory cells in atopic dermatitis (AD). We previously identified 6-sulfo LacNAc-expressing monocytes (slanMo) as TNF-α- and IL-23-producing cells in psoriatic skin lesions and as inducers of IFN-γ-, IL-17-, and IL-22-producing T cells. These cytokines are also upregulated in AD and normalize with treatment, as recently shown for dupilumab-treated patients. We here asked for the role of slanMo in AD. Increased numbers of slanMo were found in AD skin lesions. In difference to other MPs in AD, slanMo lacked expression of FcɛRI, CD1a, CD14, and CD163. slanMo from blood of patients with AD expressed increased levels of CD86 and produced IL-12 and TNF-α at higher amounts than CD14+ monocytes and myeloid dendritic cells. While CD14+ monocytes from patients with AD revealed a reduced IL-12 production, we observed no difference in the cytokine production comparing slanMo in AD and healthy controls. Interestingly, experimentally induced mental stress, a common trigger of flares in patients with AD, rapidly mobilized slanMo which retained their high TNF-α-producing capacity. This study identifies slanMo as a distinct population of inflammatory cells in skin lesions and as proinflammatory blood cells in patients with AD. slanMo may, therefore, represent a potent future target for treatment of AD.

Acetyl-11-keto-β-boswellic acid inhibits the secretion of cytokines by dendritic cells via the TLR7/8 pathway in an imiquimod-induced psoriasis mouse model and in vitro

AimsPsoriasis vulgaris is mediated by T and dendritic cells. This study aimed to investigate the effects of acetyl-11-keto-β-boswellic acid (AKBA) on activated dendritic cells (DCs) using an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow–derived dendritic cells (BMDCs) stimulated with resiquimod (R848) in vitro. Materials and methodsThe mice were treated with IMQ and intragastrically administered 25–100 mg/kg/day of AKBA, 1 mg/kg/day of methotrexate (MTX), or normal saline. The inflammation of skin lesions in IMQ mice were evaluated by psoriasis area and severity index (PASI) and pathological staining. The related proteins of Toll-like receptor (TLR)7/8 pathways were assessed using Western blotting, and the expression levels of interleukin (IL)-23 and IL-12p40 mRNA using reverse transcription–polymerase chain reaction. The numbers of DCs and marker-positive BMDCs were assessed using flow cytometry and the levels of inflammatory factors using the enzyme-linked immunosorbent assay. Key findingsAKBA and MTX obviously improved the psoriasis-like skin lesions of IMQ-treated mice. AKBA also obviously decreased the PASI score, reduced the thickness of epidermis, ameliorated the infiltration of CD3+ and CD11c+ cells in skin lesions, decreased the activation of local DCs, inhibited the mRNA expression and secretion of inflammatory factors IL-12 and IL-23, inhibited the maturation and differentiation of DCs to promote T-cell differentiation, and inhibited the activation of TLR7/8 and IRF signaling pathways. SignificanceThis study implied that AKBA might have an anti-inflammatory effect on psoriasis by inhibiting the maturation and activation of DCs via the TLR8 and IRF signaling pathways.

401 CD8+CD103+ skin resident memory T cells are a subpopulation of CD8+MDR-1+ cells in lesional skin of psoriasis and correlate with the clinical course

401 CD8+CD103+ skin resident memory T cells are a subpopulation of CD8+MDR-1+ cells in lesional skin of psoriasis and correlate with the clinical course

Cutaneous infiltration of plasmacytoid dendritic cells and T regulatory cells in skin lesions of polymorphic light eruption.

Polymorphic light eruption (PLE) is the most common autoimmune photodermatosis. Plasmacytoid dendritic cells (PDCs) are important mediators of innate antimicrobial immunity involved in the pathogenesis of many inflammatory skin diseases. In addition to PDCs, regulatory T cells (Tregs) are involved in controlling inflammation and adaptive immunity in skin by their immunosuppressive capacity. The aim of this study was to investigate the presence of PDCs and Tregs in photoexposed skin from PLE compared to healthy skin. Patients with PLE diagnosis and healthy controls were recruited and underwent a photoprovocative test. A 4-mm punch biopsy was taken from the site of positive photoprovocation test reaction, and immunohistochemistry for BDCA2 as marker for PDCs, CD4 and FOXP3 as markers for Tregs was performed. Double immunostain for FOXP3 and CD4 was performed as well. Absolute counts for CD4, BDCA2 and FOXP3 were performed in at least 5 High Power Fields (HPF). Percentage of CD4-, BDCA2- and CD4FOXP3-positive cells over the total inflammatory infiltrate was assessed for each case. We enrolled 23 patients and controls. BDCA2+ cells were present in 91.3% of PLE skin samples and 100% of healthy volunteer. Both in PLE patients and healthy controls, PDCs distribution was mainly dermic (P < 0.05). Compared to healthy controls, both epidermic and dermic BDCA2+ cells count were significantly higher in PLE patients (P < 0.05). Both in PLE patients and healthy controls, Tregs distribution was mainly dermic (P < 0.05). The presence of both CD4+ cells and FOXP3+ cells was significantly higher in the dermis of PLE patients compared to controls (P < 0.05). Relative percentages of cellular infiltrations confirmed these results. D-PDCS and Tregs may play a significant role in the development of PLE, and dermal distribution of PDCs in PLE skin biopsies seems to confirm a possible overlap with cutaneous lupus erythematosus (CLE).

Topical administration of reversible SAHH inhibitor ameliorates imiquimod-induced psoriasis-like skin lesions in mice via suppression of TNF-α/IFN-γ-induced inflammatory response in keratinocytes and T cell-derived IL-17

DZ2002, a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. The present study was designed to characterize the potential therapeutic effects of DZ2002 on murine model of psoriasis and reveal the correlated mechanisms. In this report, we demonstrated that in vitro, DZ2002 significantly decreased the expression of pro-inflammatory cytokines and adhesion molecule including IL-1α, IL-1β, IL-6, IL-8, TNF-α and ICAM-1 by inhibiting the phosphorylation of p38 MAPK, ERK and JNK in TNF-α/IFN-γ-stimulated HaCaT human keratinocytes. Topical administration of DZ2002 alleviated the imiquimod (IMQ)-induced psoriasis-like skin lesions and inflammation in mice, the therapeutic effect was comparable with the Calcipotriol. Moreover, the inflammatory skin disorder was restored by DZ2002 treatment characterized by reducing both of the CD3+ T cell accumulation and the psoriasis-specific cytokines expression. Further, we found that DZ2002 improved IMQ-induced splenomegaly and decreased the frequency of splenic IL-17-producing T cells. Our finding offered the convincing evidence that SAHH inhibitor DZ2002 might attenuate psoriasis by simultaneously interfering the abnormal activation and differentiation of keratinocytes and accumulation of IL-17-producing T cells in skin lesions.

Periostin in the pathogenesis of skin diseases.

Skin is an organ that is susceptible to damage by external injury, chronic inflammation, and autoimmunity. Tissue damage causes alterations in both the configuration and type of cells in lesional skin. This phenomenon, called tissue remodeling, is a universal biological response elicited by programmed cell death, inflammation, immune disorders, and tumorigenic, tumor proliferative, and cytoreductive activity. In this process, changes in the components of the extracellular matrix are required to provide an environment that facilitates tissue remodeling. Among these extracellular matrix components, periostin, a glycoprotein that is predominantly secreted from dermal fibroblasts, has attracted attention. Periostin localizes in the papillary dermis of normal skin, and is aberrantly expressed in the dermis of lesional skin in atopic dermatitis, scar, systemic/limited scleroderma, melanoma, cutaneous T cell lymphoma, and skin damage caused by allergic/autoimmune responses. Periostin induces processes that result in the development of dermal fibrosis, and activate or protract the immune response. The aim of this review was to summarize recent knowledge of the role of periostin in the pathogenesis of dermatoses, and to explore whether periostin is a potential therapeutic target for skin diseases.

385 IL-17E activates M2 macrophages to produce IL-8 in a p38 dependent manner and favor the recruitment of neutrophils in psoriatic skin

Psoriasis vulgaris is a common chronic recurrent immune-mediated skin disease. We have recently found that IL-17E (i.e IL-25), a member of the IL-17 cytokine family, is over-expressed in lesional psoriatic skin when compared to non lesional and healthy donors. Within the psoriatic plaque, macrophages having a mixed M1/M2 phenotype internalize IL-17E in a receptor induced clathrin-mediated mechanism. In this study we investigated the biological effects of IL-17E in psoriasis. In vitro M2-polarized macrophages, but not M1, responded to IL-17E by producing inflammatory cytokines (e.g. TNF and IL-6) and chemokines (e.g. IL-8 and MCP-1) typical expressed by M1 cells. Nuclear factor-kappa B (NF- κB), p38 and STAT3 were required for generating the IL-17E-dependent effects. Of note, IL-17E did not stimulate the production of cytokines/chemokines involved in T cell polarization and recruitment. Supernatants of IL-17E-stimulated M2 macrophages contained high levels of IL-8 and favored the attraction of neutrophils to a higher extent compared to supernatants of resting macrophages. Chemical p38 inhibition impaired IL-8 production and neutrophil chemotaxis in vitro. In vivo, intra-dermal injection of rmIL-17E in BALB/c mice induced severe dermal inflammation as assessed by immunohistological and FACS analysis, with increased neutrophil/eosinophil infiltration and reduced T-cell recruitment, compared to saline control group. Neutralization of IL-17E by intra-peritoneal injection of anti-IL-17E antibodies reduced the infiltration of neutrophils in a tape-stripping model. Consistent with the in vivo and in vitro data, the number of IL-17E+ cells in lesional skin correlated with the number of neutrophils, while being inversely proportional to the number of infiltrating T cells. Together, our data show that IL-17E favors the preferential recruitment of neutrophils via macrophage activation and define a novel pro-inflammatory role of IL-17E in psoriasis.

Pivotal Role of Lesional and Perilesional T/B Lymphocytes in Pemphigus Pathogenesis

Pemphigus is a skin and mucosal membrane-targeting autoimmune bullous disease. Previous studies have shown that circulating anti-desmoglein1/3 antibodies are pathogenic and mediate blister formation. However, the role of infiltrating immune cells in lesional skin has not been fully investigated. In this study we showed that there existed a large number of B and T lymphocytes and plasma cells in the skin lesions by immunohistochemistry and immunofluorescence staining. In addition, a significantly increased number of Dsg1- and Dsg3-specific B cells could be identified by flow cytometric analysis or enzyme-linked immunospot technique (i.e., ELISPOT) assay. Furthermore, anti-Dsg1 and Dsg3 antibodies could be detected from the supernatant of invitro cultures with isolated lymphocytes from lesional skin. We found that most T lymphocytes infiltrating pemphigus vulgaris lesions were CD4+ T helper cells expressing IL-21 and IL-17a but not typical T follicular helper cells expressing CXCR5. Additionally, our microarray assay showed that the level of chemokine CCL19 was significantly elevated, suggesting active T-/B-lymphocyte trafficking and aggregation in the pemphigus vulgaris lesions. Collectively, our results suggest a critical role of locally infiltrating lymphocytes in pemphigus pathogenesis.

RNase 7 downregulates TH2 cytokine production by activated human T cells.

The antimicrobial peptide (AMP) RNase 7 is constitutively expressed in the epidermis of healthy human skin and has been found to be upregulated in chronic inflammatory skin diseases such as atopic dermatitis and psoriasis. Activated T cells in lesional skin of patients with atopic dermatitis (AD) and psoriasis (PSO) might be directly exposed to RNase 7. In addition to their antimicrobial activity, immunoregulatory functions have been published for several AMPs. In this study, we investigated immunoregulatory effects of the antimicrobial peptide RNase 7 on activated T cells. Isolated human CD3+T cells were stimulated with RNase 7 and screened for possible effects by mRNA microarray analysis. The results of the mRNA microarray were confirmed in isolated CD4+T cells and in polarized TH2 cells using skin-derived native RNase 7 and a recombinant ribonuclease-inactive RNase 7 mutant. Activation of GATA3 was analysed by electrophoretic mobility shift assay. Treatment of activated human CD4+T cells and TH2 cells with RNase 7 selectively reduced the expression of TH2 cytokines (IL-13, IL-4 and IL-5). Experiments with a ribonuclease-inactive recombinant RNase 7 mutant showed that RNase 7 ribonuclease activity is dispensable for the observed regulatory effect. We further demonstrate that CD4+T cells from AD patients revealed a significantly less pronounced downregulation of IL-13 in response to RNase 7 compared to healthy control. Finally, we show that GATA3 activation was diminished upon cultivation of T cells with RNase 7. Our data indicate that RNase 7 has immunomodulatory functions on TH2 cells and decreases the production of TH2 cytokines in the skin.

Effect of orally administered exopolysaccharides produced by Lactococcus lactis subsp. cremoris FC on a mouse model of dermatitis induced by repeated exposure to 2,4,6-trinitro-1-chlorobenzene

Lactococcus lactis subsp. cremoris (L. cremoris) FC is a lactic acid bacteria that produces exopolysaccharides (EPS). We studied the effects of EPS on the development of dermatitis in BALB/c mice induced by repeated exposure to 2,4,6-trinitro-1-chlorobenzene (TNCB) and on intestinal immunological activity in C3H/HeJ mice through Peyer’s patch cells. The EPS was shown to be composed of phosphopolysaccharides containing rhamnose, galactose, and glucose in a molar ratio of 1:1:3. Their weight average molecular weight (Mw) was 712,000. Oral administration of EPS suppressed skin thickening and infiltration of mast cells in skin lesions. EPS suppressed IL-4, IFN-γ, IL-6, and TNF-α overexpression caused by exposure to TNCB. Peyer’s patch cell medium cultured with EPS stimulated bone marrow cell proliferation. Together, these results suggest that EPS produced by L. cremoris FC may be an effective dietary component to prevent chronic skin inflammatory diseases.

IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases.

Abstract Foxp3+ regulatory T cells (Tregs) are a major fraction of T cells in the skin. At steady state, Treg cells make little to no inflammatory cytokines and control against inflammation. However, under certain autoimmune inflammatory settings (including psoriasis) Treg cells have been shown to become dysfunctional, making pro-inflammatory cytokines and contributing to disease pathogenesis. To better understand the role of Treg cells in psoriasis we analyzed the homeostasis and function of these cells in a mouse model of psoriasiform dermatitis (IL-23 mediated skin inflammation). We find that IL-23 induced inflammation drove both proliferation and increased accumulation of Foxp3+T cells in the skin. Furthermore, IL-23 induced a population of Foxp3+T cells that expressed RORgt and made IL17A. The induction of this putative pathogenic population was completely abrogated by a RORgt inverse agonist that inhibits RORgt signaling in vivo. IL-23 was also sufficient to drive the generation of Foxp3+RORgt+IL17A+ cells in vitro, suggesting a cell intrinsic role for IL-23. Interestingly, IL-23 did not induce production of other pro-inflammatory cytokines like IFN-g by Treg cells. This is in line with recent studies where both increased accumulation and the ability of Foxp3+ T cells to make IL17A was reported in lesional skin of psoriasis patients. Current efforts are focused on better defining the characteristics of Foxp3+RORgt+IL17A+ cells in lesional skin of psoriatic patients and mice treated with IL-23. Collectively, our data suggests that IL-23 drives Treg cell plasticity by inducing a population of Foxp3+RORgt+IL17A+ cells that is regulated by RORgt signaling and could be relevant to disease pathogenesis.