IL‐17 and IL‐22 mediate IL‐20 subfamily cytokine production in cultured keratinocytes via increased IL‐22 receptor expression

IL‐20 cytokine subfamily members, including IL‐19, IL‐20, and IL‐24, are highly expressed in psoriatic skin lesions. Here, we demonstrate that psoriasis mediators IL‐17 and IL‐22 synergistically induce the production of IL‐20 subfamily proteins in cultured human keratinocytes. Interestingly, expression of the IL‐22 receptor (IL‐22R) also increased in epidermal lesions versus normal skin. IL‐22R over‐expression using an adenoviral vector to mimic psoriatic conditions in cultured keratinocytes significantly enhanced IL‐17‐ and IL‐22‐induced production of IL‐20 subfamily cytokines. Furthermore, IL‐17 and IL‐22 coordinately enhanced MIP‐3α, IL‐8, and heparin‐binding EGF‐like growth factor (HB‐EGF) production, depending on the amount of IL‐22R expression. Additionally, because IL‐20 and IL‐24 share the IL‐22R with IL‐22, the function of IL‐20 and IL‐24 was also increased. IL‐20 and IL‐24 have effects similar to that of IL‐22; IL‐24 showed more potent expression than IL‐20. A combination of IL‐24 and IL‐17 increased the production of MIP‐3α, IL‐8, and HB‐EGF, as did a combination of IL‐22 and IL‐17. These data indicate that increased IL‐22R expression in epidermal keratinocytes contributes to the pathogenesis of psoriasis through enhancing the coordinated effects of IL‐22 and IL‐17, inducing the production of the IL‐20 subfamily, chemokines, and growth factors.     

Distinct expression of interleukin (IL)‐36α, β and γ, their antagonist IL‐36Ra and IL‐38 in psoriasis,rheumatoid arthritis and Crohn's disease

Interleukin (IL)‐36α, IL‐36β and IL‐36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL‐36Ra or IL‐38, another potential IL‐36 inhibitor, limit uncontrolled inflammation. The expression and role of IL‐36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod‐induced mouse skin inflammation and in human psoriasis, expression of IL‐36α, γ and IL‐36Ra, but not IL‐36β and IL‐38 mRNA, was induced and correlated with IL‐1β and T helper type 17 (Th17) cytokines (IL‐17A, IL‐22, IL‐23, CCL20). In mice with collagen‐induced arthritis and in the synovium of patients with RA, IL‐36α, β, γ, IL‐36Ra and IL‐38 were all elevated and correlated with IL‐1β, CCL3, CCL4 and macrophage colony‐stimulating factor (M‐CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium‐induced colitis and in patients with CD, only IL‐36α, γ and IL‐38 were induced at relatively low levels and correlated with IL‐1β and IL‐17A. We suggest that only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL‐36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL‐36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68⁺ macrophages, dendritic/Langerhans cells and CD79α⁺ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL‐36β and IL‐36Ra were produced constitutively, but IL‐36α, γ and IL‐38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL‐36 agonists/antagonists ratio.     

Bcl‐3 induced by IL‐22 via STAT3 activation acts as a potentiator of psoriasis‐related gene expression in epidermal keratinocytes

IL‐22 induces STAT3 phosphorylation and mediates psoriasis‐related gene expression. However, the signaling mechanism leading from pSTAT3 to the expression of these genes remains unclear. We focused on Bcl‐3, which is induced by STAT3 activation and mediates gene expression. In cultured human epidermal keratinocytes, IL‐22 increased Bcl‐3, which was translocated to the nucleus with p50 via STAT3 activation. The increases in CXCL8, S100As and human β‐defensin 2 mRNA expression caused by IL‐22 were abolished by siRNA against Bcl‐3. Although CCL20 expression was also augmented by IL‐22, the knockdown of Bcl‐3 increased its level. Moreover, the combination of IL‐22 and IL‐17A enhanced Bcl‐3 production, IL‐22‐induced gene expression, and the expression of other psoriasis‐related genes, including those encoding IL‐17C, IL‐19, and IL‐36γ. The expression of these genes (except for CCL20) was also suppressed by the knockdown of Bcl‐3. Bcl‐3 overexpression induced CXCL8 and HBD2 expression but not S100As expression. We also compared Bcl‐3 expression between psoriatic skin lesions and normal skin. Immunostaining revealed strong signals for Bcl‐3 and p50 in the nucleus of epidermal keratinocytes from psoriatic skin. The IL‐22‐STAT3‐Bcl‐3 pathway may be important in the pathogenesis of psoriasis.     

Synergistic effect of interleukin‐17 and tumour necrosis factor‐α on inflammatory response in hepatocytes through interleukin‐6‐dependent and independent pathways

The proinflammatory cytokines interleukin (IL)‐17 and tumour necrosis factor (TNF)‐α are targets for treatment in many chronic inflammatory diseases. Here, we examined their role in liver inflammatory response compared to that of IL‐6. Human hepatoma cells (HepaRG, Huh7.5 and HepG2 cells) and primary human hepatocytes (PHH) were cultured with IL‐6, IL‐17 and/or TNF‐α. To determine the contribution of the IL‐6 pathway in the IL‐17/TNF‐α‐mediated effect, an anti‐IL‐6 receptor antibody was used. IL‐17 and TNF‐α increased in synergy IL‐6 secretion by HepaRG cells and PHH but not by Huh7.5 and HepG2 cells. This IL‐17/TNF‐α synergistic cooperation enhanced the levels of C‐reactive protein (CRP) and aspartate aminotransferase (ASAT) in HepaRG cell and PHH cultures through the induction of IL‐6. IL‐17/TNF‐α also up‐regulated IL‐8, monocyte chemoattractant protein (MCP)‐1 and chemokine (C‐C motif) ligand 20 (CCL20) chemokines in synergy through an IL‐6‐independent pathway. Interestingly, first exposure to IL‐17, but not to TNF‐α, was crucial for the initiation of the IL‐17/TNF‐α synergistic effect on IL‐6 and IL‐8 production. In HepaRG cells, IL‐17 enhanced IL‐6 mRNA stability resulting in increased IL‐6 protein levels. The IL‐17A/TNF‐α synergistic effect on IL‐6 and IL‐8 induction was mediated through the activation of extracellular signal‐regulated kinase (ERK)‐mitogen‐activated protein kinase, nuclear factor‐κB and/or protein kinase B (Akt)–phosphatidylinositol 3‐kinase signalling pathways. Therefore, the IL‐17/TNF‐α synergistic interaction mediates systemic inflammation and cell damage in hepatocytes mainly through IL‐6 for CRP and ASAT induction. Independently of IL‐6, the IL‐17A/TNF‐α combination may also induce immune cell recruitment by chemokine up‐regulation. IL‐17 and/or TNF‐α neutralization can be a promising therapeutic strategy to control both systemic inflammation and liver cell attraction.     

Hepatic serum amyloid A1 upregulates interleukin‐17 (IL‐17) in γδ T cells through Toll‐like receptor 2 and is associated with psoriatic symptoms in transgenic mice

Serum amyloid A (SAA) is an acute phase protein with pro‐inflammatory cytokine‐like properties. Recent studies have revealed that SAA promoted interleukin‐17 (IL‐17) production by various cells, including γδ T cells. γδ T cells are innate immune cells and express Toll‐like receptor 2 (TLR2) on their surface, which is one of the SAA receptors. In this study, we investigated the relationship between γδ T cells and SAA1 through TLR2, by using hepatic SAA1‐overexpressing transgenic (TG) mice. By injecting CU‐CPT22, which is a TLR2 inhibitor, into the mice, we confirmed that SAA1 induced IL‐17 in γδ T cells through TLR2. In vitro studies have confirmed that SAA1 increased IL‐17 secretion in γδ T cells in combination with IL‐23. We also observed a thickened epidermis layer and granulocyte penetration into the skin similar to the pathology of psoriasis in TG mice. In addition, strongly expressed SAA1 and penetration of γδ T cells in the skin of TG mice were detected. The exacerbation of psoriasis is associated with an increase in IL‐17 levels. Therefore, these symptoms were induced by IL‐17‐producing γδ T cells increased by SAA1. Our study confirmed that SAA1 was a prominent protein that increased IL‐17 levels through TLR2 in γδ T cells, confirming the possibility that SAA1 may exacerbate inflammatory diseases through γδ T cells.     

Proinflammatory effect of high‐mobility group protein B1 on keratinocytes: an autocrine mechanism underlying psoriasis development

Psoriasis is an autoimmune skin disease, in which keratinocytes play a crucial pathogenic role. High‐mobility group protein B1 (HMGB1) is an inflammatory factor that can be released from keratinocyte nuclei in psoriatic lesions. We aimed to investigate the proinflammatory effect of HMGB1 on keratinocytes and the contribution of HMGB1 to psoriasis development. Normal human keratinocytes were treated with recombinant human HMGB1, and the production of inflammatory factors and the intermediary signalling pathways were examined. Furthermore, the imiquimod‐induced psoriasis‐like mouse model was used to investigate the role of HMGB1 in psoriasis development in vivo. A total of 11 inflammatory factors were shown to be upregulated by HMGB1 in keratinocytes, among which interleukin (IL)‐18 showed the greatest change. We then found that activation of the nuclear factor‐κB signalling pathway and inflammasomes accounted for HMGB1‐induced IL‐18 expression and secretion. Moreover, HMGB1 and downstream IL‐18 contributed to the development of psoriasiform dermatitis in the imiquimod‐treated mice. In addition, T‐helper 17 immune response in the psoriasis‐like mouse model could be inhibited by both HMGB1 and IL‐18 blockade. Our findings indicate that HMGB1 secreted from keratinocytes can facilitate the production and secretion of inflammatory factors such as IL‐18 in keratinocytes in an autocrine way, thus promoting the development of psoriasis. Blocking the proinflammatory function of the HMGB1–IL‐18 axis may be useful for psoriasis treatment in the future. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Protective effect of a germline,IL‐17‐neutralizing antibody in murine models of autoimmune inflammatory disease

Monoclonal antibodies (mAbs) inhibiting cytokines have recently emerged as new drug modalities for the treatment of chronic inflammatory diseases. Interleukin‐17 (IL‐17) is a T‐cell‐derived central mediator of autoimmunity. Immunization with Qβ‐IL‐17, a virus‐like particle based vaccine, has been shown to produce autoantibodies in mice and was effective in ameliorating disease symptoms in animal models of autoimmunity. To characterize autoantibodies induced by vaccination at the molecular level, we generated mouse mAbs specific for IL‐17 and compared them to germline Ig sequences. The variable regions of a selected hypermutated high‐affinity anti‐IL‐17 antibody differed in only three amino acid residues compared to the likely germline progenitor. An antibody, which was backmutated to germline, maintained a surprisingly high affinity (0.5 nM). The ability of the parental hypermutated antibody and the derived germline antibody to block inflammation was subsequently tested in murine models of multiple sclerosis (experimental autoimmune encephalomyelitis), arthritis (collagen‐induced arthritis), and psoriasis (imiquimod‐induced skin inflammation). Both antibodies were able to delay disease onset and significantly reduced disease severity. Thus, the mouse genome unexpectedly encodes for antibodies with the ability to functionally neutralize IL‐17 in vivo.     

Lipopolysaccharide (LPS)‐induced Interferon (IFN)‐gamma Production by Decidual Mononuclear Cells (DMNC) is Interleukin (IL)‐2 and IL‐12 Dependent

Citation Negishi M, Izumi Y, Aleemuzzaman S, Inaba N, Hayakawa S. Lipopolysaccharide (LPS)‐induced interferon (IFN)‐gamma production by decidual mononuclear cells (DMNC) is interleukin (IL)‐2 and IL‐12 dependent. Am J Reprod Immunol 2011; 65: 20–27 Problem Th1‐shifted immune response is believed to be harmful for successful pregnancy because of activation of maternal cytotoxic T lymphocytes and natural killer cells. However, its effects on Toll‐like receptor (TLR)‐mediated innate immune response are so far unknown and this study has been undertaken to address the issue. Method of study Decidual tissues were obtained from 16 pregnant women undergoing elective termination during the first trimester pregnancy for socioeconomic reasons. Decidual Mononuclear Cells (DMNC) were stimulated with suboptimal doses of IL‐2 and IL‐12 with/without LPS, considered to be a TLR4 ligand, for 48 hr. Productions of IFN‐γ and tumor necrosis factor (TNF)‐α in culture supernatant were measured with ELISA. Results (i) IFN‐γ production was induced with LPS alone which was strongly up‐regulated in the presence of IL‐2 and IL‐12. (ii) TNF‐α was also induced by LPS but was not affected by the presence of IL‐2 and IL‐12. Conclusion IL‐2 and IL‐12 up‐regulated the production of IFN‐γ in DMNC through increasing their susceptibility to LPS. TNF‐α production is independent of such a mechanism.     

Association of Disease Severity with IL‐1 levels in Methotrexate‐treated Psoriasis Patients

Interleukin‐1 plays a key role in inflammation and keratinocyte activation. It is an important mediator in the initiation and maintenance of psoriatic plaques and may represent an attractive therapeutic target. The aim of this study is to evaluate the effect of Methotrexate (MTX) on IL‐1 α and IL‐1 β levels in both plasma and skin biopsy of patients with psoriasis and to investigate their association with clinical disease activity. Forty‐five control subjects and 58 patients with psoriasis were recruited for this study. The patients were treated with 7.5 mg of MTX per week for 12 weeks. Folic acid was given at 5 mg once daily except on the day of MTX for 12 weeks. Blood samples and lesional skin biopsy were taken. Disease severity was assessed by Psoriasis Area Severity Index (PASI) score. IL‐1 levels in plasma and skin biopsy were analysed using ELISA. PASI score declined significantly (P < 0.001) from day 0 to 12 weeks of MTX treatment. IL‐1 α level in plasma and skin biopsy was reduced at day 0 sample and elevated significantly (P < 0.001) after MTX treatment. IL‐1β level in plasma and skin biopsy was higher at day 0 sample and reduced significantly (P < 0.001) after MTX treatment. IL‐1α levels and PASI score showed inverse correlation score before and after treatment with MTX. Whereas IL‐1β levels showed positive correlation before and after treatment with MTX. Decreasing IL‐1β levels by MTXs in psoriasis may block the Th17 differentiation. This shows the therapeutic effect of MTX in controlling the immunopathogenesis of psoriasis.     

Interleukin‐17A: a unique pathway in immune‐mediated diseases: psoriasis,psoriatic arthritis and rheumatoid arthritis

Experimental evidence points to the importance of the cytokine interleukin‐17A (IL‐17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL‐17A is produced by many other cell types including CD8⁺ T cells and γδ T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL‐17A up‐regulates expression of numerous inflammation‐related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL‐17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro‐inflammatory cytokines, including tumour necrosis factor. Several direct IL‐17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL‐17A in disease pathogenesis, although levels of response are not predicted by pre‐clinical findings. IL‐17A inhibitors produced rapid down‐regulation of the psoriasis gene signature and high clinical response rates in patients with moderate‐to‐severe plaque psoriasis, consistent with an important role for IL‐17A in psoriasis pathogenesis. Clinical response rates with IL‐17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL‐17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL‐17A in these diseases.     

IL‐33 promotes innate IFN‐γ production and modulates dendritic cell response in LCMV‐induced hepatitis in mice

Recent studies have revealed IL‐33 as a key factor in promoting antiviral T‐cell responses. However, it is less clear as to how IL‐33 regulates innate immunity. In this study, we infected wild‐type (WT) and IL‐33^?/? mice with lymphocytic choriomeningitis virus and demonstrated an essential role of infection‐induced IL‐33 expression for robust innate IFN‐γ production in the liver. We first show that IL‐33 deficiency resulted in a marked reduction in the number of IFN‐γ⁺ γδ T and NK cells, but an increase in that of IL‐17⁺ γδ T cells at 16 h postinfection. Recombinant IL‐33 (rIL‐33) treatment could reverse such deficiency via increasing IFN‐γ‐producing γδ T and NK cells, and inhibiting IL‐17⁺ γδ T cells. We also found that rIL‐33‐induced type 2 innate lymphoid cells were not involved in T‐cell responses and liver injury, since the adoptive transfer of type 2 innate lymphoid cells neither affected the IFN‐γ and TNF‐α production in T cells, nor liver transferase levels in lymphocytic choriomeningitis virus infected mice. Interestingly, we found that while IL‐33 was not required for costimulatory molecule expression, it was critical for DC proliferation and cytokine production. Together, this study highlights an essential role of IL‐33 in regulating innate IFN‐γ‐production and DC function during viral hepatitis.     

CXCL4 is a novel inducer of human Th17 cells and correlates with IL‐17 and IL‐22 in psoriatic arthritis

CXCL4 regulates multiple facets of the immune response and is highly upregulated in various Th17‐associated rheumatic diseases. However, whether CXCL4 plays a direct role in the induction of IL‐17 production by human CD4⁺ T cells is currently unclear. Here, we demonstrated that CXCL4 induced human CD4⁺ T cells to secrete IL‐17 that co‐expressed IFN‐γ and IL‐22, and differentiated naïve CD4⁺ T cells to become Th17‐cytokine producing cells. In a co‐culture system of human CD4⁺ T cells with monocytes or myeloid dendritic cells, CXCL4 induced IL‐17 production upon triggering by superantigen. Moreover, when monocyte‐derived dendritic cells were differentiated in the presence of CXCL4, they orchestrated increased levels of IL‐17, IFN‐γ, and proliferation by CD4⁺ T cells. Furthermore, the CXCL4 levels in synovial fluid from psoriatic arthritis patients strongly correlated with IL‐17 and IL‐22 levels. A similar response to CXCL4 of enhanced IL‐17 production by CD4⁺ T cells was also observed in patients with psoriatic arthritis. Altogether, we demonstrate that CXCL4 boosts pro‐inflammatory cytokine production especially IL‐17 by human CD4⁺ T cells, either by acting directly or indirectly via myeloid antigen presenting cells, implicating a role for CXCL4 in PsA pathology.     

The impact of disease activity and tumour necrosis factor‐α inhibitor therapy on cytokine levels in juvenile idiopathic arthritis

The aim of this study was to evaluate prospectively cytokine levels and disease activity in juvenile idiopathic arthritis (JIA) patients treated with and without tumour necrosis factor (TNF)‐α inhibitors. TNF‐α inhibitor‐naive JIA subjects were followed prospectively for 6 months. Cytokine levels of TNF‐α, interleukin (IL)?1β, IL‐6, IL‐8, IL‐10 and IL‐17 were measured at baseline for JIA subjects and healthy controls (HCs). Cytokine levels were then measured at four time‐points after initiation of TNF‐α inhibition for anti‐TNF‐α‐treated (anti‐TNF) JIA subjects, and at two subsequent time‐points for other JIA (non‐TNF) subjects. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Sixteen anti‐TNF, 31 non‐TNF and 16 HCs were analysed. Among JIA subjects, those with higher baseline disease activity (subsequent anti‐TNFs) had higher baseline TNF‐α, IL‐6 and IL‐8 than those with lower disease activity (non‐TNFs) (P < 0·05). TNF‐α and IL‐10 increased, and IL‐6 and IL‐8 no longer remained significantly higher after TNF‐α inhibitor initiation in anti‐TNF subjects. Subgroup analysis of etanercept versus adalimumab‐treated subjects showed that TNF‐α and IL‐17 increased significantly in etanercept but not adalimumab‐treated subjects, despite clinical improvement in both groups of subjects. JIA subjects with increased disease activity at baseline had higher serum proinflammatory cytokines. TNF‐α inhibition resulted in suppression of IL‐6 and IL‐8 in parallel with clinical improvement in all anti‐TNF‐treated subjects, but was also associated with elevated TNF‐α and IL‐17 in etanercept‐treated subjects.     

Decreased Plasma IL‐22 Levels and Correlations with IL‐22‐Producing T Helper Cells in Patients with New‐Onset Systemic Lupus Erythematosus

Interleukin‐22 (IL‐22) and IL‐22‐producing T helper (Th) cells are involved in the pathogenesis of autoimmune diseases. However, the roles of IL‐22 and IL‐22‐producing T helper cells in systemic lupus erythematosus (SLE) remain unclear. Plasma levels of IL‐22 were measured in 41 patients with SLE (19 new‐onset and 22 relapsing patients) and 20 healthy controls by enzyme‐linked immunosorbent assay (ELISA). Meanwhile, the percentages of CD4⁺IFN‐γ⁺ (Th1), CD4⁺IL‐17⁺ (Th17) and CD4⁺IFN‐γ^?IL‐17^? IL‐22⁺ (Th22) cells in peripheral lymphocytes were determined by flow cytometry, and plasma IL‐22 autoantibodies were detected by ELISA in 19 new‐onset SLE patients and 20 healthy controls. Plasma IL‐22 levels in new‐onset SLE patients were significantly decreased compared with relapsing SLE patients and healthy controls. After treatment with prednisone and hydroxychloroquine, the levels of plasma IL‐22 in new‐onset SLE patients were obviously increased but still lower than healthy controls. There was a positive correlation between plasma IL‐22 levels and the percentages of Th22 cells, but not Th1 and Th17 cells. Moreover, plasma IL‐22 levels as well as peripheral Th17 and Th22 cells correlated with SLE disease activity index (SLEDAI) scores and erythrocyte sedimentation rate (ESR). High frequencies of plasma IL‐22 autoantibodies were detected in new‐onset SLE patients. However, IL‐22 levels did not correlate with IL‐22 autoantibody. Decreased plasma IL‐22 levels and correlation with Th22 cells may be distinct features in new‐onset SLE. Moreover, IL‐22 and Th22 cell correlated with SLE disease activity.     

T‐bet protects against exacerbation of schistosome egg‐induced immunopathology by regulating Th17‐mediated inflammation

C57BL/6 mice infected with Schistosoma mansoni naturally develop mild CD4⁺ T‐cell‐mediated immunopathology characterized by small hepatic granulomas around parasite eggs. However, immunization with soluble egg Ag in CFA markedly exacerbates the lesions by inducing a potent proinflammatory environment with high levels of IFN‐γ and IL‐17, which are signature cytokines of distinct Th1‐ versus Th17‐cell lineages. To determine the relative role of these subsets in disease exacerbation, we examined mice deficient in T‐bet (T‐bet^?/?), which is required for Th1 differentiation and IFN‐γ production. We now report that immunization with soluble egg Ag in CFA caused a significantly greater enhancement of egg‐induced hepatic immunopathology in T‐bet^?/? mice compared with WT controls, and analysis of their granulomas disclosed a higher proportion of activated DC and CD4⁺ T cells, as well as a marked influx of neutrophils. The absence of IFN‐γ in the T‐bet^?/? mice correlated with a marked increase in IL‐23p19, IL‐17 and TNF‐α in granulomas and MLN. In contrast, T‐bet^?/? mice had lower levels of IL‐4, IL‐5 and IL‐10 and a reduction in FIZZ1 and FoxP3 expression, suggesting diminished regulatory activity, respectively, by alternatively activated macrophages and Treg. These findings demonstrate that T‐bet‐dependent signaling negatively regulates Th17‐mediated immunopathology in severe schistosomiasis.     

Psoriatic cutaneous inflammation promotes human monocyte differentiation into active osteoclasts,facilitating bone damage

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy that can be associated with focal bone erosions. Psoriasis usually precedes the psoriatic arthritis onset by an average of 10 years, but this relation is not yet fully elucidated. Pro‐inflammatory cytokines, such as IL‐33, OPN, IL‐17, and TNF‐α are involved in both psoriasis and PsA pathogenesis as well as in bone homeostasis. In this study, we have demonstrated that IL‐33, OPN, IL‐17, and TNF‐α induced the release of a wide range of pro‐osteoclastogenic factors from the skin, such as RANKL, that promote monocyte differentiation in osteoclasts. The addition of osteoprotegerin, a RANKL inhibitor, to monocyte cultures treated with supernatant from stimulated skin did not completely deplete osteoclast formation, suggesting that skin produced several additional pro‐osteoclastogenic mediators, which could act in a RANKL‐independent manner. Moreover, we have found that RANKL serum levels as well as osteoclast number and activity in psoriatic patients with and without arthritis, was influenced by severity of cutaneous disease. Our data demonstrate that psoriatic cutaneous inflammation contributes to bone damage.