The aryl hydrocarbon receptor (AhR), for many years almost exclusively studied by the pharmacology/toxicology field for its role in mediating the toxicity of xenobiotics such as ...2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has more recently attracted the attention of immunologists. The evolutionary conservation of this transcription factor and its widespread expression in the immune system point to important physiological functions that are slowly being unraveled. In particular, the emphasis is now shifting from the role of AhR in the xenobiotic pathway toward its mode of action in response to physiological ligands. In this article, we review the current understanding of the molecular interactions and functions of AhR in the immune system in steady state and in the presence of infection and inflammation, with a focus on barrier organs such as the skin, the gut, and the lung.
Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanisms are largely unknown. Here we show that the aryl hydrocarbon receptor ...(AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists increased inflammation. Similarly, AhR signaling via the endogenous ligand FICZ reduced the inflammatory response in the imiquimod-induced model of skin inflammation and AhR-deficient mice exhibited a substantial exacerbation of the disease, compared to AhR-sufficient controls. Nonhematopoietic cells, in particular keratinocytes, were responsible for this hyperinflammatory response, which involved upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders.
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•Physiological AhR signals reduce psoriasis gene expression in patient biopsies•Blocking AhR signals exacerbates psoriasis gene expression in patient biopsies•AhR-deficient mice show exacerbated skin inflammation in imiquimod model•Absence of AhR on mouse or human keratinocytes causes excessive inflammation
The aryl hydrocarbon receptor (AhR), a transcription factor that responds to environmental signals, interacts with a wide range of genes involved in inflammatory responses. Di Meglio et al. show that physiological stimulation of AhR ameliorates skin inflammation in mice and humans.
Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a ...comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases.
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•Resource of heritabilities and genetic associations of 80,000 immune traits in 669 twins•Genetic associations with immune cell frequencies and surface protein expression levels•Of the top 150 traits, 11 genetic loci explained up to 36% of variation of 19 traits•Loci include autoimmune susceptibility genes, providing etiological hypotheses
The study of a large and homogenous population of human twins identifies numerous genetic loci controlling the phenotype or number of functionally important immune subsets in the blood, providing a database to test associations of any genetic locus with more than 78,000 different immune traits.
Generalized pustular psoriasis (GPP) is a rare and yet potentially lethal clinical variant of psoriasis, characterized by the formation of sterile cutaneous pustules, neutrophilia, fever and features ...of systemic inflammation. We sequenced the exomes of five unrelated individuals diagnosed with GPP. Nonsynonymous, splice-site, insertion, and deletion variants with an estimated population frequency of <0.01 were considered as candidate pathogenic mutations. A homozygous c.338C>T (p.Ser113Leu) missense substitution of IL36RN was identified in two individuals, with a third subject found to be a compound heterozygote for c.338C>T (p.Ser113Leu) and a c.142C>T (p.Arg48Trp) missense substitution. IL36RN (previously known as IL1F5) encodes an IL-1 family receptor antagonist, which opposes the activity of the IL-36A and IL-36G innate cytokines. Homology searches revealed that GPP mutations alter evolutionarily conserved residues. Homozygosity for the c.338C>T (p.Ser113Leu) variant is associated with an elevated proinflammatory response following ex vivo stimulation with IL36A. These findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention.
The skin provides the first line defense of the human body against injury and infection. By integrating recent findings in cutaneous immunology with fundamental concepts of skin biology, we portray ...the skin as a multitasking organ ensuring body homeostasis. Crosstalk between the skin and its microbial environment is also highlighted as influencing the response to injury, infection, and autoimmunity. The importance of the skin immune network is emphasized by the identification of several skin-resident cell subsets, each with its unique functions. Lessons learned from targeted therapy in inflammatory skin conditions, such as psoriasis, provide further insights into skin immune function. Finally, we look at the skin as an interacting network of immune signaling pathways exemplified by the development of a disease interactome for psoriasis.
Biologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. Here we perform in-depth ...immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. The heightened NF-κB activation is linked to increased DC maturation in vitro and frequency of IL-17
T cells in the blood of non-responders before therapy. Moreover, lesional skin of non-responders contains higher numbers of dermal DC expressing the maturation marker CD83 and producing IL-23, and increased numbers of IL-17
T cells. Finally, we identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome.
Targeting CD8+ T cells prevents psoriasis development Di Meglio, Paola, PhD; Villanova, Federica, PhD; Navarini, Alexander A., MD, PhD ...
Journal of allergy and clinical immunology,
07/2016, Letnik:
138, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Importantly, in the absence of T-cell expansion upon transplantation, which did not occur in one of the experiments we performed, we did not observe any epidermal pathology, in terms of both ...papillomatosis and frequency of proliferating keratinocytes (see Fig E1 in this article's Online Repository at www.jacionline.org). ...the accumulation of epidermal T cells induces both keratinocyte hyperproliferation and onset of papillomatosis, 2 hallmarks of psoriasis, thereby further confirming the role of intraepidermal T cells as key effectors in psoriasis. Psoriatic CD8+ T cells have been previously characterized in terms of their cytokine production; however, little distinction has been made between those residing in the dermis and the epidermis in the absence of post-isolation in vitro culture. ...to obtain a faithful functional characterization of psoriatic CD8+ T cells, we isolated T cells from the epidermis and the dermis of psoriasis lesions and performed intracellular cytokine staining and fluorescence-activated cell sorting analyses.
Abnormal production of inflammatory mediators is believed to play an important role in the pathogenesis of psoriasis. Emerging data, both in mice and in humans, put the spotlight on a new subset of T ...helper (Th) cells, in part characterized by their production of IL-17 and accordingly named Th17 cells. Here, we review the development, characterization, and function of human Th17 cells as well as the crucial role of IL-23 in the context of Th17-cell-dependent chronic inflammation in psoriasis. We further discuss recent clinical trials targeting the IL-23/Th17 axis in psoriasis.
Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with ...age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age.
Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues.
Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.
Atopic dermatitis (AD) is a common inflammatory skin disease. Both epidermal barrier dysfunction and immunodysregulation are suggested to influence the pathogenesis of AD. AD has been considered a ...paradigmatic T helper cell (Th) 2-mediated disease, with a switch to a Th1 cell environment during the chronic phase of the disease. Previously unreported findings now suggest a possible role for Th17 cells as well.
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