Human NCF190H Variant Promotes IL-23/IL-17–Dependent Mannan-Induced Psoriasis and Psoriatic Arthritis
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Recently, a major single nucleotide variant on the NCF1 gene, leading to an amino acid replacement from arginine to histidine at position 90 (NCF1R90H), associated with low production of reactive oxygen species (ROS), was found to be causative for several autoimmune diseases. Psoriasis in the skin (PsO) and psoriatic arthritis (PsA) were induced with mannan by intraperitoneal injection or epicutaneous application, evaluated by visual and histology scoring. Immunostaining was used to identify macrophages, NCF1, and keratinocytes. The population of immune cells was quantified by flow cytometry, gene expression was analyzed by RT-qPCR, and the JAK/STAT signaling pathway was investigated by immunohistochemical staining and western blot. We found that the low ROS responder NCF190H variant promotes PsO and PsA (the MIP model). The NCF190H-expressing mice had hyperactivated macrophages, expanded keratinocytes, and dramatically increased numbers of γδT17 cells with upregulated IL-17A, IL-23, and TNF-α. In addition, the JAK1/STAT3 signaling pathway was also upregulated in cells in the psoriatic skin tissues of Ncf190H mice. To summarize, a defined SNP (NCF1-339, also named NCF190H) was found to activate the IL-23/IL-17 axis and JAK-STAT signaling pathways, leading to hyperactivation of macrophages and keratinocytes and causing mouse psoriasis and psoriatic arthritis.Psoriasis is a frequent chronic inflammatory skin disease, nowadays considered a major global health problem. Several new drugs, targeting the IL-23/IL-17A pathway, have been recently licensed or are in clinical development. These therapies represent a major improvement of the way in which psoriasis is managed, since they show an unprecedented efficacy on skin symptoms of psoriasis. This has been made possible, thanks to an increasingly more accurate pathogenic view of psoriasis. Today, the belief that Th17 cells mediate psoriasis is moving to the concept of psoriasis as an IL-17A-driven disease. New questions arise at the horizon, given that IL-17A is part of a newly described family of cytokines, which has five distinct homologous: IL-17B, IL-17C, IL-17D, IL-17E, also known as IL-25 and IL-17F. IL-17 family cytokines elicit similar effects in target cells, but simultaneously trigger different and sometimes opposite functions in a tissue-specific manner. This is complicated by the fact that IL-17 cytokines show a high capacity of synergisms with other inflammatory stimuli. In this review, we will summarize the current knowledge around the cytokines belonging to the IL-17 family in relation to skin inflammation in general and psoriasis in particular, and discuss possible clinical implications. A comprehensive understanding of the different roles played by the IL-17 cytokines is crucial to appreciate current and developing therapies and to allow an effective pathogenesis- and mechanisms-driven drug design.
Interleukin-23
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Proinflammatory cytokine
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Psoriasis is a chronic skin disease characterized by hyperproliferation of keratinocytes and increased inflammation. Previous studies have detected the levels of cytokines in the serum of patients with psoriasis, yet few multi-cytokine combination studies have been reported.The aim of the study was to compare the levels of cytokines in the serum between patients with psoriasis and healthy controls, elucidate which factors influence the psoriasis progression.A total of 39 psoriasis patients and 30 healthy volunteers were enrolled. The venous blood was collected and the levels of 13 inflammatory cytokines were measured by human inflammation panel 1 kit. The severity of the disease was determined according to the psoriasis area and severity index (PASI) score.Compared with healthy controls, the levels of nine cytokines (IFN-γ, TNF-α, IL-1β, IL-6, IL-10, IL-12P40, IL-18, IL-17A and IL-23) were significantly increased, while the level of MCP-1 decreased in psoriatic patients. In addition, except for MCP-1, IL-10 and IL-12P40, these cytokine levels were positively correlated with the PASI score. Furthermore, there were higher serum lever of IFN-γ, TNF-α, IL-1β, IL-6, IL-17A, IL-18 and IL-23 in active psoriasis than healthy controls and retrograde psoriasis.Increased serum levels of IFN-γ, TNF-α, IL-1β, IL-6, IL-17A, IL-18 and IL-23 in psoriatic patients were associated with PASI and the stage of disease, which suggested that these cytokines play an important role in the pathogenesis of psoriasis. The detection of these cytokines can better observe the disease activity of psoriasis and optimize the treatment strategy.
Interleukin-23
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Proinflammatory cytokine
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Introduction: T-helper 1 (Th1), Th17 cells, and their related cytokines are implicated in psoriasis pathogenesis although the contribution of each group of cytokines in psoriasis activity has not been fully clarified. Objectives: To investigate whether Th17-related cytokines are associated with psoriasis activity. Methods: The serum levels of interleukin (IL)-1β, 6, 8, 17Α, 22, 23, and tumor necrosis factor-α (TNFα) were measured with flow cytometry in 35 patients with plaque psoriasis (21 with stable and 14 with active disease) and in 20 healthy controls. Results: Interleukin-6, 8, 17A, 22, 23, and TNFα were significantly elevated in psoriasis patients compared with controls. In the sensitivity analyses, patients with active disease showed significantly increased levels of IL-17A, IL-23, and IL-22 as compared to the group of patients with stable psoriasis. Conclusions: Our study highlights a possible crucial role of IL-17A, IL-22, and IL-23 in the activity of psoriasis and the early stages of the disease.
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Interleukin-23
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To examine the serum levels of interleukin (IL)-30 in patients with psoriasis and evaluate the correlations with the Psoriasis Area and Severity Index (PASI).Serum was collected from 26 patients with psoriasis and 26 healthy controls in a case-control setting, and the level of IL-30 was determined using an enzyme-linked immunosorbent assay. Statistical analysis of the IL-30 levels among groups and further correlation analyses of IL-30 levels with PASI scores were performed.A significant increase in the level of IL-30 in patients with psoriasis compared with healthy controls was observed. In addition, a positive correlation between the IL-30 concentration and PASI scores was found in patients with psoriasis.IL-30 is presumably involved in the proliferation of epidermal cells during the development of psoriasis. Further studies with a larger number of participants are required to comprehensively elucidate the biological roles of IL-30 in the pathogenesis of psoriasis.
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Positive correlation
Interleukin 22
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Objective Th17 has been shown to have a pivotal role in the development of arthritis. However, the role of IL-17 in the T cell-independent effector phase has not fully been examined. We investigated whether IL-17 is involved in the effector phase of arthritis by using K/BxN serum-induced arthritis model. Methods K/BxN serum was transferred into IL-17 knockout (KO) mice, SCID mice and their control mice, and arthritis was evaluated over time. In order to clarify the source of IL-17 in the effector phase, neutrophils or CD4+ T cells collected from IL-17 KO or control mice were injected into IL-17 KO recipient mice together with K/BxN serum. To examine if neutrophils secrete IL-17 upon stimulation, neutrophils were stimulated with immune complex in vitro and IL-17 in the supernatant was measured by ELISA. Results K/BxN serum-induced arthritis was much less severe in IL-17 KO mice than in WT mice. Since K/BxN serum-transferred SCID mice developed severe arthritis with high serum IL-17 concentration, we speculated neutrophils are the responsible player as an IL-17 source. When wild type (WT) but not IL-17 KO neutrophils were co-injected with K/BxN serum into IL-17 KO mice, arthritis was exacerbated, whereas co-injection of WT CD4+ T cells had no effect. In vitro, stimulation of neutrophils with immune complexcaused IL-17 secretion. Conclusions Neutrophils are essential as a source of IL-17 in the effector phase of arthritis. The trigger of secreting IL-17 from neutrophils may be immune complex.
Inflammatory arthritis
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Intestinal microbiota are associated with the development of inflammatory arthritis. The aim of this study was to dissect intestinal mucosal immune responses in the preclinical phase of arthritis and determine whether the presence of Th17 cells, beyond involvement of the cytokine interleukin-17 (IL-17), is required for arthritis development, and whether the involvement of Th17 cells in arthritis depends on the composition of the host microbiota.Mucosal T cell production of IL-17, interferon-γ, tumor necrosis factor α (TNFα), IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) was analyzed by flow cytometry and Luminex assay before arthritis onset in mice immunized to develop collagen-induced arthritis (CIA). Pathogenic features of arthritis in mice with CIA and mice with antigen-induced arthritis were compared between Th17 cell-deficient (CD4-Cre+ Rorcflox/flox ) and Th17 cell-sufficient (CD4-Cre- Rorcflox/flox ) mice. In addition, the impact of intestinal microbiota on the Th17 cell dependence of CIA was assessed.Lamina propria CD4 T cells were activated before the onset of arthritis in mice with CIA, with marked up-regulation of several cytokines, including IL-17A, TNFα, and GM-CSF. CD4-Cre+ Rorcflox/flox mice showed a specific reduction in intestinal mucosal levels of Th17 cells and partially reduced levels of IL-17-producing CD8 T cells. However, total levels of IL-17A, mostly produced by γδ T cells and neutrophils, were unaffected. The severity of arthritis was significantly reduced in Th17 cell-deficient mice, suggesting that Th17 cells have additional, IL-17A-independent roles in inflammatory arthritis. Accordingly, antigen-stimulated T cells from Th17 cell-deficient mice produced less IL-17A, IL-17F, and GM-CSF. Importantly, the dependence of CIA on the involvement of Th17 cells was mitigated in the presence of an alternative microbiome.These data from murine models suggest that activation of mucosal immunity precedes the development of arthritis, and also that Th17 cells have a microbiota-dependent role in arthritis. Therefore, a microbiome-guided stratification of patients might improve the efficacy of Th17-targeted therapies.
Inflammatory arthritis
Collagen-induced arthritis
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This chapter contains sections titled: Introduction History of psoriasis Who gets psoriasis? Biology of psoriasis Comorbidities associated with psoriasis Clinical variants of psoriasis Physical symptoms that accompany psoriasis Trigger factors in psoriasis Treatments for psoriasis Measuring quality of life Conclusion References
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Psoriasis is a multifactor skin disorder, with immune-mediated inflammatory pathogenesis. Theories and studies illustrated the crucial role for Interleukin-17 (IL-17) in promotes the occurrence and severity of psoriasis. We measured the serum IL-17 levels for detection the importance and effects of IL-17 as predictors for the psoriasis disorders and its severity. Forty-five cases of psoriatic patients and the same number from healthy subjects as control were included in this study, the severity of psoriasis was determined by the Psoriasis Area and Severity Index (PASI). Patients were categorize according to severity as mild psoriasis in (21), and moderate to severe psoriasis group in (24), 3 ml sera samples of both groups were collected to estimate IL-17, The results showed that the majority of the patients comprised of age group 36-45 (42.0%), Female to male ratio in patients was 1.6:1. Serum IL-17 was significantly increasing among psoriatic patients as compared to healthy controls (895.066 pg/ml and 364.334 pg/ml) respectively. Also, there was a relation between an elevated IL-17 serum levels and Psoriasis severity of groups with highly significant difference. It can be concluded that (IL-17) has important role during the activity of psoriasis and should be a target for biological therapy in Iraqi psoriatic patients.
Pathogenesis
Interleukin 22
Interleukin-23
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Psoriasis is a chronic inflammatory skin disease caused by multiple factors. With the widespread use of biological agents, the therapeutic effect of psoriasis is gradually recognized, among which interleukin-17A (IL-17A) inhibitor has remarkable efficacy, which has aroused great attention in the academic world. However, some cases abroad have shown that IL-17A inhibitors may induce or secondary to other skin diseases in the treatment of psoriasis. In this review, we will review the case reports of other skin diseases induced or secondary to IL-17A inhibitors in the treatment of psoriasis in recent years, in order to provide a reference for clinicians in the use of this drug.
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