Summary
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.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Interleukin (IL)-22 is a T cell-derived cytokine that has been reported recently to induce cutaneous inflammation in an experimental murine model of psoriasis, and to induce in vitro an ...inflammatory-like phenotype. In the present study, we assessed the presence of IL-22 and the IL-22 receptor 1 (IL-22R1) in skin lesions, skin-derived T cells, as well as IL-22 levels in sera from patients with psoriasis. IL-22R1 and IL-10R2 transcripts are expressed at a similar level in psoriatic and healthy skin. In contrast, IL-22 mRNA expression was up-regulated in psoriatic skin lesions compared to normal skin, whereas IL-22 mRNA levels in peripheral blood mononuclear cells from psoriatic patients and normal subjects were similar. Circulating IL-22 levels were significantly higher in psoriatic patients than in normal subjects. T cells isolated from psoriatic skin produced higher levels of IL-22 in comparison to peripheral T cells isolated from the same patients. IL-10 was expressed at similar levels in skin biopsies and peripheral blood mononuclear cells of psoriatic patients and normal subjects. Finally, we show here that supernatants of lesional psoriatic skin-infiltrating T cells induce an inflammatory response by normal human epidermal keratinocytes, resembling that observed in psoriatic lesions. Taken together, the results reported in this study indicate that IL-22 is a cytokine produced by skin-infiltrating lymphocytes that is potentially involved in initiation and/or maintenance of the pathogenesis of psoriasis.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Alcoholic liver cirrhosis (ALC) is characterized by increased circulating levels of immunoglobulins (Igs). ALC patients undergo bacterial translocation evidenced by the presence of bacterial DNA in ...peripheral blood. Bacterial pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), peptidoglycan (PGN) and unmethylated cytosine-guanine dinucleotide (CpG) DNA are ligands of Toll-like receptor (TLR)-4, TLR-2 and TLR-9, respectively. Although TLR activation results generally in the secretion of proinflammatory cytokines, activation of B cells through TLR-7 or TLR-9 is involved in their maturation and Ig synthesis. The aim of the present study was to assess Ig synthesis by ALC B cells under PAMP activation in order to evaluate the possible involvement of TLR pathways in the increased Ig levels, and especially the hyper-IgA observed in ALC. CpG, in combination with interleukin (IL)-10 or IL-21, enhanced IgA, IgG and IgM synthesis by healthy donor (HD) PBMCs, but had only a weak effect on ALC PBMCs. Relative CpG-induced IgA production by purified ALC B cells was less important when compared to HD B cells, in accordance with the lower TLR-9 expression on ALC B cells compared to HD B cells, but the absolute IgA production by CpG-activated B cells was enhanced significantly for ALC when compared to HD, in agreement with their intrinsic ability to produce spontaneously more IgA than HD. LPS and PGN had no direct activity on B cells, whereas R848 also enhanced Ig synthesis, as reported recently. Taken together, these results suggest that TLR priming of B cells could account for the hyperimmunoglobulinaemia observed in ALC patients.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Psoriasis exhibits several extracutaneous manifestations. Little is known about hepatic parameters specifically associated with psoriasis.
Objectives
To study whether psoriasiform ...dermatitis is associated with liver injury.
Methods
We studied liver parameters of inflammation and fibrosis in a murine model of psoriasiform dermatitis induced by topical application of imiquimod for 9 weeks.
Results
Topical treatment with imiquimod induced a form of psoriasiform dermatitis reminiscent of the human disorder, characterized by thickened and scaly skin, psoriasiform epidermal hyperplasia, altered keratinocyte differentiation and cutaneous overexpression of interleukin‐17A. Mice with dermatitis displayed hepatitis, as shown by elevation of plasma transaminase levels, as well as portal and periportal hepatitis, characterized by T‐lymphocyte (CD3ε+) and polymorphonuclear cell (Gr1+) infiltrates. The hepatitis progressed towards liver fibrogenesis, as shown by excessive Sirius red staining, which is consistent with the expression of α‐smooth muscle actin by hepatic stellate cells.
Conclusions
These results indicate that liver inflammation and fibrosis are associated with experimental psoriasiform dermatitis. Our results suggest that psoriatic inflammation may be associated with specific liver injury.
What's already known about this topic?
Psoriasis is a systemic disease.
Severe liver fibrosis is more frequent in patients with psoriasis.
What does this study add?
Long‐term maintenance of the imiquimod‐induced murine model of psoriasiform dermatitis recapitulates the main features of psoriasis.
Mice with psoriasiform dermatitis display portal hepatitis characterized by T‐cell, monocyte and polymorphonuclear cell infiltrates.
Hepatitis observed in imiquimod‐treated mice evolves towards liver fibrosis.
What is the translational message?
Psoriasis may be a cofactor of liver fibrosis.
Linked Comment: Maybury et al. Br J Dermatol 2018; 179:9–10.
Respond to this article
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
1 Etablissement Français du Sang, Ile de France, Hôpital Henri Mondor, Créteil;
2 Centre de Référence des Cytopénies Auto-Immunes, Hôpital Henri Mondor, Créteil;
3 Service des Maladies Génétiques du ...Globule Rouge, Hôpital Henri Mondor Créteil;
4 Service de Médecine Interne, Hôpital Henri Mondor, Créteil;
5 Laboratoire dImmunologie, Hôpital Henri Mondor, Créteil;
6 Université de Poitiers, EA 3806, CHU de Poitiers
Correspondence: France Noizat-Pirenne, MD, PhD, Etablissement Français du Sang dIle de France, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. Tel: 331 56 72 76 37; Fax: 331 56 72 76 01, E-mail: france.noizat-pirenne{at}efs.sante.fr
Delayed hemolytic transfusion reaction (DHTR), a life-threatening transfusion complication in sickle cell disease (SCD), is characterized by a marked hemoglobin drop with destruction of both transfused and autologous red blood cells (RBCs) and exacerbation of SCD symptoms. One mechanism of RBCs destruction is auto-antibody production secondary to transfusion. As rituximab specifically targets circulating B cells, we thought that it could be beneficial in preventing this immune-mediated transfusion complication. We report the case of a SCD patient who previously experienced DHTR with auto-antibodies and who needed a new transfusion. DHTR recurrence was successfully prevented by rituximab administration prior transfusion, supporting the safe use of rituximab to prevent DHTR in SCD patients as a second line approach when other measures failed.
Key words: Sickle cell disease, rituximab, transfusion, auto-antibodies.
In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic dysfunction and neuro-inflammation. The fibroblast growth factor 21 (FGF21) plays an ...important role in the regulation of both phenomena and is a major hormone of energetic homeostasis. In this study, we aimed to determine the relevance of FGF21 pathway stimulation in a male mouse model of ALS (mutated
SOD1-G93A
mice) by using a pharmacological agonist of FGF21, R1Mab1. Mice (SOD1-WT and mutant SOD1-G93A) were treated with R1Mab1 or vehicle. Longitudinal data about clinical status (motor function, body weight) and biological parameters (including hormonal, immunological, and metabolomics profiles) were collected from the first symptoms to euthanasia at week 20. Multivariate models were performed to identify the main parameters associated with R1Mab1 treatment and to link them with clinical status, and metabolic pathways involving the discriminant metabolites were also determined. A beneficial clinical effect of R1Mab1 was revealed on slow rotarod (
p
= 0.032), despite a significant decrease in body weight of ALS mice (
p
< 0.001). We observed a decrease in serum TNF-α, MCP-1, and insulin levels (
p
= 0.0059,
p
= 0.003, and
p
= 0.01, respectively). At 16 weeks, metabolomics analyses revealed a clear discrimination (CV-ANOVA = 0.0086) according to the treatment and the most discriminant pathways, including sphingolipid metabolism, butanoate metabolism, pantothenate and CoA biosynthesis, and the metabolism of amino acids like tyrosine, arginine, proline, glycine, serine, alanine, aspartate, and glutamate. Mice treated with R1Mab1 had mildly higher performance on slow rotarod despite a decrease on body weight and could be linked with the anti-inflammatory effect of R1Mab1. These results indicate that FGF21 pathway is an interesting target in ALS, with a slight improvement in motor function combined with metabolic and anti-inflammatory effects.
IL-22 belongs to a family of cytokines structurally related to IL-10, including IL-19, IL-20, IL-24, and IL-26. In contrast to IL-10, IL-22 has proinflammatory activities. IL-22 signals through a ...class II cytokine receptor composed of an IL-22-binding chain, IL-22RA1, and the IL-10RB subunit, which is shared with the IL-10R. In the present study, we show that short-term cultured human epidermal keratinocytes express a functional IL-22R but no IL-10R. Accordingly, IL-22 but not IL-10 induces STAT3 activation in keratinocytes. Using a cDNA array screening approach, real-time RT-PCR, and Western blot analysis, we demonstrate that IL-22 up-regulates, in a dose-dependent manner, the expression of S100A7, S100A8, S100A9, a group of proinflammatory molecules belonging to the S100 family of calcium-binding proteins, as well as the matrix metalloproteinase 3, the platelet-derived growth factor A, and the CXCL5 chemokine. In addition, IL-22 induces keratinocyte migration in an in vitro injury model and down-regulates the expression of at least seven genes associated with keratinocyte differentiation. Finally, we show that IL-22 strongly induces hyperplasia of reconstituted human epidermis. Taken together, these results suggest that IL-22 plays an important role in skin inflammatory processes and wound healing.
Integrity of the epidermal barrier is based on a tight regulation of the communication between keratinocytes and immune cells, particularly provided by the balanced cytokine production. An imbalance ...network leads to appearance of skin inflammatory diseases such as psoriasis. Our work has identified a part of this cytokine network in psoriatic lesions. Modeling of skin inflammation showed that combination of IL-1a, IL-17A, IL-22, OSM and TNF a synergistically increases expression of chemokines and antimicrobial peptides, leading to massive neutrophil skin infiltration, recapitulating some features of psoriasis.
The aim of our study was to investigate the impact of these cytokines on keratinocyte differentiation.
If IL-1a, IL-17A, IL-22, OSM or TNFa were able to decrease expressions of cytokeratin 10 (K10), loricrin (LOR), filaggrin (FLG) and cadherin 1 (CDH1), IL-22, OSM and TNFa were the most powerful. Combination of these 5 cytokines (M5) generated a synergistic effect on inhibition of expression for these markers of differentiation. These results were confirmed on reconstructed epidermis (RHE). IL-22 and OSM significantly decreased expressions of K10, FLG and CDH1 and induced epidermal hyperplasia. Injection of the M5 in vivo in mice caused a thickening of the skin associated with decreased expression of K10, FLG and CDH1. Similarly we have demonstrated a significant decrease in the expression of these markers in skin lesions of psoriasis patients, showing an expression profile similar to those obtained in vitro and in vivo. Our results showed that synergistic effect of M5 was responsible for the production of antimicrobial peptides, chemokines and the inhibition of keratinocyte differentiation. If IL-1a, IL-17A and TNFa were important for the production of antimicrobial peptides and chemokines, IL-22, OSM and TNFa seemed essential to the differentiation inhibition.
Establishment of these models should clarify the role of these cytokines in the establishment of the inflammatory response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
IL‐22 is an IL‐10 homologue that binds to and signals via the class II cytokine receptor (R) heterodimer IL‐22RA1/CFR2‐4 (IL‐10R2), the latter chain being part of the IL‐10R complex. Here, we report ...that, despite its structural similarity with IL‐10, as well as its use of the common IL‐10R2 chain, IL‐22, in contrast to IL‐10, is unable to induce Ig production by activated human B cells. Whereas culture of anti‐CD40 mAb‐stimulated splenic or tonsillar B cells in the presence of rIL‐10 resulted in the production of IgG, IgG1, IgG3 and IgA, rIL‐22, at concentrations ranging from 4 to 100 ng/ml, did not induce the production of any of these isotypes. Moreover, unlike rIL‐10 which enhanced rIL‐4‐induced IgG4 and IgE production, rIL‐22 was ineffective. Although activated B cells expressed transcripts for a soluble IL‐22‐binding protein (IL‐22RA2), no mRNA for a transmembrane IL‐22R (IL‐22RA1) could be detected. The latter result was confirmed by the demonstration that rIL‐22 failed to induce activation of STAT‐3 and ‐5 in resting or activated B cells. Together, these data show that IL‐22, in contrast to its homologue IL‐10, is not involved in the immunological activity of B cells, which is due to the absence of a functional IL‐22R at the surface of these cells.
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