Search

Psoriasis is a chronic inflammatory disease characterised by sharply demarcated erythematous and scaly skin lesions accompanied by systemic manifestations. Classified by WHO as one of the most serious non-infectious diseases, psoriasis affects 2-3% of the global population. Mechanistically, psoriatic lesions result from hyperproliferation and disturbed differentiation of epidermal keratinocytes that are provoked by immune mediators of the IL-23 and IL-17 pathway. Translational immunology has had impressive success in understanding and controlling psoriasis. Psoriasis is the first disease to have been successfully treated with therapeutics that directly block the action of the cytokines of this pathway; in fact, therapeutics that specifically target IL-23, IL-17, and IL-17RA are approved for clinical use and show excellent efficacy. Furthermore, inhibitors of IL-23 and IL-17 intracellular signalling, such as TYK2 or RORγt, are in clinical development. Although therapies that target the IL-23 and IL-17 pathway also improve psoriatic arthritis symptoms, their effects on long-term disease modification and psoriasis-associated comorbidities still need to be explored., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that may paradoxically induce either apoptosis or cell survival. It mediates its activity through binding of TNF-receptor (TNFR) 1 or 2. TNFR1 is mainly responsible for transmitting apoptotic signals. The activation of apoptotic mechanisms can either be intrinsic (mitochondrial) or extrinsic (death receptors). Death ligands such as TNF-related apoptosis-inducing ligand (TRAIL) specifically induce extrinsic apoptosis, while cytostatic drugs such as 5-fluorouracil (5FU) induce intrinsic apoptosis., Objectives: To investigate the effects of TNFα on apoptosis in malignant and normal human keratinocytes., Methods: Human cutaneous squamous cell carcinoma (SCC) cell line SCC-13 and immortalized human keratinocytes HaCaT as well as primary normal human keratinocytes (PNHK) were stimulated with TNFα and then treated either with TRAIL or 5FU. Cell viability and cell proliferation, DNA fragmentation, apoptosis, and cytotoxicity were determined by WST-1 proliferation assay, ELISA, flow cytometry, and colorimetric analysis of lactate dehydrogenase, respectively. In addition, Western blotting was performed for analysis of caspase-3., Results: TNFα affected viability of SCC-13 and HaCaT cells in combination with 5FU or TRAIL. In contrast, TNFα did not influence cell viability of PNHK. It enhanced the apoptotic effects of both extrinsic and intrinsic stimuli in SCC-13 and HaCaT. In clear contrast, TNFα protected PNHK against TRAIL- and 5FU-induced apoptosis. The effects were dose-dependent and TNFα-specific; furthermore, the apoptosis pathway was caspase-dependent., Conclusions: In summary, opposing effects of TNFα in malignant versus normal human keratinocytes were observed with possibly relevant clinical implications, when patients are treated with TNFα inhibitors., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Psoriasis is a very common chronic inflammatory skin disease characterized by epidermal thickening and scaling resulting from keratinocyte hyperproliferation and impaired differentiation. Pathomechanistic studies in psoriasis are often limited by using whole skin tissue biopsies, neglecting their stratification and cellular diversity. This study aimed at characterizing epidermal alterations in psoriasis at the level of keratinocyte populations. Epidermal cell populations were purified from skin biopsies of psoriasis patients and healthy donors using a novel cell type-specific approach. Molecular characterization of the transit-amplifying cells (TAC), the key players of epidermal renewal, was performed using immunocytofluorescence-technique and integrated multiscale-omics analyses. Already TAC from non-lesional psoriatic skin showed altered methylation and differential expression in 1.7% and 1.0% of all protein-coding genes, respectively. In psoriatic lesions, TAC were strongly expanded showing further increased differentially methylated (10-fold) and expressed (22-fold) genes numbers. Importantly, 17.2% of differentially expressed genes were associated with respective gene methylations. Compared with non-lesional TAC, pathway analyses revealed metabolic alterations as one feature predominantly changed in TAC derived from active psoriatic lesions. Overall, our study showed stage-specific molecular alterations, allows new insights into the pathogenesis, and implies the involvement of epigenetic mechanisms in lesion development in psoriasis. KEY MESSAGES: Transit amplifying cell (TAC) numbers are highly increased in psoriatic lesions Psoriatic TAC show profound molecular alterations & stage-specific identity TAC from unaffected areas already show first signs of molecular alterations Lesional TAC show a preference in metabolic-related alterations.

Background: Acne inversa (AI)/hidradenitis suppurativa is a chronic inflammatory disease characterized by painful axillary, inguinal and perianal skin lesions with deep-seated nodules, abscesses and fistulae., Objectives: This study aimed to identify and characterize the key players in AI pathogenesis., Methods: Epidemiological and anamnestic data for patients with AI were collected, and blood and skin samples were also taken. Healthy participants and patients with psoriasis served as controls. Assessment of samples and cultures of primary cells was performed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction on reverse transcribed mRNA, and immunohistochemistry., Results: Of 35 mediators quantified in the blood of patients with AI, lipocalin-2 (LCN2) appeared as one of the most significantly upregulated parameters compared with healthy participants [85·8 ± 12·2 (n = 18) vs. 41·8 ± 4·2 (n = 15); P < 0·001]. Strongly elevated LCN2 expression was present in AI lesions, with granulocytes and keratinocytes being sources of this expression. In vitro, these cells upregulated LCN2 production in response to tumour necrosis factor (TNF)-α, and a positive relationship between systemic TNF-α and LCN2 levels (r s = 0·55, P = 0·011; n = 20) was evident for AI. LCN2 blood levels correlated with AI disease severity (r s = 0·65, P < 0·001; n = 29), but not with disease duration, age, sex, body mass index or smoking habit. Detailed analyses revealed a link with the number of skin regions containing nodules and fistulae, but not scars., Conclusions: LCN2 might serve as a blood biomarker for the objective assessment of inflammatory activity in AI. We suggest a self-amplification loop comprising TNF-α, neutrophilic granulocytes and LCN2, which contributes to the recurrent skin neutrophil infiltration in AI, clinically evident as pus., (© 2017 British Association of Dermatologists.)

Psoriasis is a chronic inflammatory disease resulting from dysregulated immune activation associated with a large local secretion of cytokines. Among them, IL-22 largely contributes to epithelial remodeling and inflammation through inhibiting the terminal differentiation of keratinocytes and inducing antimicrobial peptides and selected chemokines. The activity of IL-22 is regulated by IL-22 binding protein (IL-22BP); however, the expression and role of IL-22BP in psoriatic skin has remained unknown so far. Here we showed that nonaffected skin of psoriasis patients displayed lower expression of IL-22BP than skin of healthy controls. Furthermore, the strong IL-22 increase in lesional psoriatic skin was accompanied by a moderate induction of IL-22BP. To investigate the role of IL-22BP in controlling IL-22 during skin inflammation, we used imiquimod-induced skin disease in rodents and showed that rats with genetic IL-22BP deficiency ( Il22ra2 ) displayed exacerbated disease that associated with enhanced expression of IL-22-inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti-IL-22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, we found positive correlations with the expression of IL-22-inducible molecules (IL-20, IL-24, IL-36γ, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis.-/- ) displayed exacerbated disease that associated with enhanced expression of IL-22-inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti-IL-22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, we found positive correlations with the expression of IL-22-inducible molecules (IL-20, IL-24, IL-36γ, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Psoriasis is a common chronic inflammatory skin disease with a prevalence of about 2% in the Caucasian population. Tumor necrosis factor (TNF) plays an essential role in the pathogenesis of psoriasis, but its mechanism of action remains poorly understood. Here we report that the development of psoriasis-like skin inflammation in mice with epidermis-specific inhibition of the transcription factor NF-κB was triggered by TNF receptor 1 (TNFR1)-dependent upregulation of interleukin-24 (IL-24) and activation of signal transducer and activator of transcription 3 (STAT3) signaling in keratinocytes. IL-24 was strongly expressed in human psoriatic epidermis, and pharmacological inhibition of NF-κB increased IL-24 expression in TNF-stimulated human primary keratinocytes, suggesting that this mechanism is relevant for human psoriasis. Therefore, our results expand current views on psoriasis pathogenesis by revealing a new keratinocyte-intrinsic mechanism that links TNFR1, NF-κB, ERK, IL-24, IL-22R1, and STAT3 signaling to disease initiation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Psoriasis is a common chronic skin disease. Recent studies demonstrated that IL-20 and IL-22, cytokines produced by keratinocytes and T cells, respectively, both inhibit keratinocyte terminal differentiation and induce psoriasis-like epidermis alterations. Here, we investigated the relationship between these mediators. Although IL-20 was not able to regulate IL-22 production, IL-22 induced IL-20 mRNA and protein in human keratinocytes. However, IL-22 had only a minimal effect, if any, on IL-19 and IL-26. Cutaneous IL-20 was also elevated in mice following IL-22 application. Accordingly, some of IL-22's effects on differentiation-regulating genes were partially mediated by an endogenous, secreted protein and attenuated by anti-IL-20 Ab. Like IL-22, IL-17A and TNF-alpha induced IL-20 in keratinocytes, whereas IFN-gamma and IL-20 itself did not. Furthermore, IL-17A and TNF-alpha individually strengthened the IL-22-induced IL-20 production. In lesional skin of psoriasis patients, highly elevated IL-20 levels strongly correlated with IL-22, and to a lesser extent, with IL-17A and TNF-alpha. As previously shown for IL-22, IL-20 blood levels correlated with the disease severity, although with a lower significance. This study demonstrates that a T-cell mediator induces a tissue cell mediator with similar effects to its own and therefore suggests the existence of a novel type of pathogenetic cascade.

IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29 are new members of the IL-10 interferon family. Monocytes are well-known sources of IL-19, IL-20, and IL-24. We demonstrated here that monocytes also expressed IL-29, and monocyte differentiation into macrophages (Mphi) or dendritic cells (DCs) strongly changed their production capacity of these cytokines. Maturation of DCs with bacterial stimuli induced high expression of IL-28/IL-29 and IL-20. Simulated T cell interaction and inflammatory cytokines induced IL-29 and IL-20 in maturing DCs, respectively. Compared with monocytes, DCs expressed only minimal IL-19 levels and no IL-24. The differentiation of monocytes into Mphi reduced their IL-19 and terminated their IL-20, IL-24, and IL-29 production capacity. Like monocytes, neither Mphi nor DCs expressed IL-22 or IL-26. The importance of maturing DCs as a source of IL-28/IL-29 was supported by the much higher mRNA levels of these mediators in maturing DCs compared with those in CMV-infected fibroblasts, and the presence of IL-28 in lymph nodes but not in liver of lipopolysaccharide-injected mice. IL-19, IL-20, IL-22, IL-24, and IL-26 do not seem to affect Mphi or DCs as deduced from the lack of corresponding receptor chains. The significance of IL-20 and IL-28/IL-29 coexpression in maturing DCs may lie in the broadly amplified innate immunity in neighboring tissue cells like keratinocytes. In fact, IL-20 induced the expression of antimicrobial proteins, whereas IL-28/IL-29 enhanced the expression of toll-like receptors (TLRs) and the response to TLR ligands. However, the strongest response to TLR2 and TLR3 activation showed keratinocytes in the simultaneous presence of IL-20 and IL-29.

Psoriasis is a common chronic skin disease. Its pathogenesis has intensively been investigated in the last 3 decades. In the 1970s, the observed increased proliferation of keratinocytes and their altered differentiation were considered to be the most important signs and causes of psoriatic skin lesions. Since the early 1980s, T cells slid into the focus of psoriasis research. It was then postulated that a subpopulation of T cells, so-called T1 cells, and their prominent cytokine interferon-gamma, had a dominant role in the pathogenesis of psoriasis. In the last decade, new data regarding macrophages and dendritic cells and the high therapeutic success of anti-tumor necrosis factor alpha biologics led to the assumption that antigen-presenting cells are important not only in the induction of psoriasis but also in its maintenance. The knowledge gained over the past 3 decades let us postulate that psoriasis is an immunologically induced, overshot, regeneration-like reaction of the skin in which various cells play a dominant role at different stages. This hypothesis is also supported by the very recent discoveries about interleukin (IL)-22, IL-20, and IL-23.

Due to their structural similarity, interleukin (IL)-19, IL-20, IL-22, IL-24 and IL-26 were combined with IL-10 in the so-called IL-10 family. To expand the knowledge on IL-19, IL-20 and IL-24, we systematically and quantitatively analysed the expression of these mediators and their receptor chains in vitro and in vivo under various conditions and in comparison with other IL-10 family members. In vitro, IL-19, IL-20 and IL-24 were produced not only by activated immune cells, particularly monocytes, but also to a similar extent by keratinocytes. IL-1beta increased the expression of these mediators 1000-fold (IL-19) and 10-fold (IL-20 and IL-24) in keratinocytes. In vivo, these cytokines were expressed preferentially in inflamed tissues. The absence of either R1 chain for the two types of receptor complexes for these cytokines (IL-20R1/IL-20R2 and IL-22R1/IL-20R2) on immune cells implies that they cannot act on these cells. In fact, IL-19, IL-20 and IL-24 did not induce activation of signal transducer and activator of transcription (STAT) molecules in immune cells. Instead, several tissues, particularly the skin, tissues from the reproductive and respiratory systems, and various glands appeared to be the main targets of these mediators. Keratinocytes expressed both receptor complexes; however, the expression of IL-22R1 was 10 times higher than that of IL-20R1. Interferon-gamma further increased the expression of IL-22R1 and decreased that of IL-20R1, suggesting that under T1 cytokine conditions these mediators primarily affect keratinocytes via the IL-22R1/IL-20R2 complex. In summary, these data support the notion that IL-19, IL-20 and IL-24 are distinct from classical ILs and constitute a separate subfamily of mediators within the IL-10 family.

IL-22 is an IFN-IL-10 cytokine family member, which is produced by activated Th1 and NK cells and acts primarily on epithelial cells. Here we demonstrate that IL-22, in contrast to its relative IFN-gamma, regulates the expression of only a few genes in keratinocytes. This is due to varied signal transduction. Gene expressions regulated by IL-22 should enhance antimicrobial defense [psoriasin (S100A7), calgranulin A (S100A8), calgranulin B (S100A9)], inhibit cellular differentiation (e.g., profilaggrin, keratins 1 and 10, kallikrein 7), and increase cellular mobility [e.g., matrix metalloproteinease 1 (MMP1, collagenase 1), MMP3 (stromelysin 1), desmocollin 1]. In contrast, IFN-gamma favored the expression of MHC pathway molecules, adhesion molecules, cytokines, chemokines, and their receptors. The IL-22 effects were transcriptional and either independent of protein synthesis and secretion, or mediated by a secreted protein. Inflammatory conditions, but not keratinocyte differentiation, amplified the IL-22 effects. IL-22 application in mice enhanced cutaneous S100A9 and MMP1 expression. High IL-22 levels in psoriatic skin were associated with strongly up-regulated cutaneous S100A7, S100A8, S100A9, and MMP1 expression. Psoriatic patients showed strongly elevated IL-22 plasma levels, which correlated with the disease severity. Expression of IL-22 and IL-22-regulated genes was reduced by anti-psoriatic therapy. In summary, despite similarities, IFN-gamma primarily amplifies inflammation, while IL-22 may be important in the innate immunity and reorganization of epithelia.

Ultraviolet irradiation represents a well-established treatment modality for inflammatory skin diseases. The aim of this study was to investigate the mechanisms of ultraviolet B radiation-induced keratinocyte insensitivity towards interferon-gamma. Flow cytometric analyses indicated that ultraviolet B radiation temporarily inhibits the interferon-gamma-induced activation of primary keratinocyte and HaCaT cells as measured by reduced intercellular adhesion molecule-1 (CD54) and HLA-DR upregulation. Western blot experiments have suggested that this is mediated by the ultraviolet B radiation-induced inhibition of signal transduction and transcription factor-1 phosphorylation. Neither interleukin-10 neutralization nor interleukin-10 addition had any effect on the ultraviolet B radiation-induced inhibition of interferon-gamma induced intercellular adhesion molecule-1 expression. Furthermore, the supernatant from ultraviolet B-irradiated cells failed to inhibit the interferon-gamma-induced CD54 and HLA-DR upregulation in nonradiated HaCaT cells. Moreover, irradiated cells from whom the supernatant was withdrawn 4 h after irradiation still showed a diminished interferon-gamma-induced response after 24 h. Thus, not soluble but intracellular factors might be involved in the ultraviolet B radiation-induced inhibition of interferon-gamma-induced keratinocyte activation. Therefore, we analyzed the expression of members of suppressors of cytokine-signaling (SOCS) molecules using real-time polymerase chain reaction. We found a fast and strong upregulation of SOCS1 and SOCS3 but not of SOCS2 after ultraviolet B radiation. Similarly, ultraviolet B radiation induced the expression of these particular SOCS molecules in lesional psoriatic skin. As SOCS molecules are known inhibitors of signal transduction and transcription factor phosphorylation, which is essential for interferon-gamma-induced intercellular adhesion molecule-1 and HLA-DR upregulation, this may explain the interferon-gamma unresponsiveness after ultraviolet B radiation.

Whereas the effects of interleukin (IL)-10 on several epithelial cell types are well established the capability of IL-10 to target keratinocytes (KC) is still a matter of debate. This, however, is of considerable importance, as IL-10 is a major anti-inflammatory, immunosuppressive cytokine with impact on the cutaneous homeostasis. Recently, IL-10 therapy has been proven to be clinically effective in psoriasis. Response to therapy is associated with normalization of typical parameters of keratinocyte pathology, but it is unclear whether this results from direct or indirect (secondary) effects. The purpose of the present study was to further investigate direct effects of IL-10 on keratinocytes and to address the reason for potential IL-10 unresponsiveness using keratinocytes such as the cell line HaCaT as well as primary foreskin keratinocytes. Using real time RT-PCR we demonstrated that IL-10 is neither able to induce its typical early gene product suppressor of cytokine signalling (SOCS) 3 nor to modulate the interferone (IFN)-gamma-induced expression of SOCS 1 and 3. Although flow cytometric analyses showed binding of biotin labelled IL-10 to HaCaT cells, blocking experiments indicated that this resulted from unspecific binding. Moreover, scatchard plot analyses excluded specific binding to primary KC and HaCaT cells. Finally, real time mRNA analyses and Western blot experiments demonstrated that the absence of any specific binding results from the absence of clear IL-10R1 (alpha chain) expression, whereas the IL-10R2 (beta chain) is strongly expressed. Our data indicates that IL-10 unresponsiveness of keratinocytes could be explained by the lacking of functional IL-10 receptor expression and suggest that any IL-10 effects on these cells observed are indirectly mediated.

Interferon (IFN)-λ1, -2 and -3 (also designated as interleukin (IL)-29, IL-28α and IL-28β) represent a new subfamily within the class II cytokine family. They show type I IFN-like antiviral and cytostatic activities in affected cells forming the basis for IFN-λ1 therapy currently under development for hepatitis C infection. However, many aspects of IFN-λs are still unknown. This study aimed at identifying the target cells of IFN-λs within the immune system and the skin. Among skin cell populations, keratinocytes and melanocytes, but not fibroblasts, endothelial cells or subcutaneous adipocytes turned out to be targets. In contrast to these target cells, blood immune cell populations did not clearly respond to even high concentrations of these cytokines, despite an IFN-λ receptor expression. Interestingly, immune cells expressed high levels of a short IFN-λ receptor splice variant (sIFN-λR1/sIL-28R1). Its characterization revealed a secreted, glycosylated protein that binds IFN-λ1 with a moderate affinity (KD 73 nM) and was able to inhibit IFN-λ1 effects. Our study suggests that IFN-λ therapy should be suited for patients with verrucae, melanomas and non-melanoma skin cancers, apart from patients with viral hepatitis, and would not be accompanied by immune-mediated complications known from type I IFN application. [ABSTRACT FROM AUTHOR]