• Inflammation
• Interleukin-17
• Tendinopathy

• Interleukin-17/metabolism
• Animals
• Humans
• Tendinopathy/etiology
• Tendinopathy/pathology
• Tendinopathy/genetics
• Rats
• Disease Models, Animal
• Male
• Signal Transduction
• Female
• Middle Aged
• Rotator Cuff/pathology
• Rotator Cuff/metabolism
• Tendons/metabolism
• Tendons/pathology

• Wellcome Trust
• Royal College of Surgeons of Edinburgh
• Novartis Pharma AG

• IL‐19
• atherosclerosis
• coronary artery disease
• psoriasis
• resistin

• Eli Lilly Japan

• Humans
• Psoriasis/drug therapy
• Psoriasis/genetics
• Female
• Male
• Antibodies, Monoclonal, Humanized/therapeutic use
• Polymorphism, Single Nucleotide
• Middle Aged
• Adult
• Dermatologic Agents/therapeutic use
• MicroRNAs/genetics
• Severity of Illness Index
• Treatment Outcome

• PI01583 Instituto de Salud Carlos III
• Fondo Europeo de Desarrollo Regional
• Novartis

• gut microbiota
• inflammatory factor
• psoriasis
• rutaecarpine (RUT)

• Humans
• Animals
• Mice
• Imiquimod/adverse effects
• Gastrointestinal Microbiome
• RNA, Ribosomal, 16S/genetics
• Psoriasis/chemically induced
• Psoriasis/drug therapy
• Dermatitis
• Cytokines/metabolism
• Disease Models, Animal
• Mice, Inbred BALB C
• Indole Alkaloids
• Quinazolinones

• Candida albicans
• IL-17 signaling
• cytokines
• defensins
• oral epithelium
• signal transduction

• Humans
• Mice
• Animals
• Candidiasis, Oral/genetics
• Candidiasis, Oral/microbiology
• Candida albicans
• Candidiasis
• Mucous Membrane
• Transcription Factors/genetics
• Adaptor Proteins, Signal Transducing

• R01 DE022550 NIDCR NIH HHS
• R15 DE026898 NIDCR NIH HHS
• R37 DE022550 NIDCR NIH HHS
• T32 AI089443 NIAID NIH HHS

• immunity
• inflammation
• itaconate.
• macrophage
• metabolism

• 81974107 National Natural Science Foundation of China
• 82270909 National Natural Science Foundation of China

• adaptive immune cells
• adipokines
• crosstalk
• cytokines
• immune-inflammatory cells
• immunocompetent cells
• interleukins
• signaling pathways
• tumor microenvironment

• Female
• Humans
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cytokines/metabolism
• Endothelial Cells/metabolism
• Inflammation/metabolism
• Tumor Microenvironment

• Ligue Ligue Nationale Contre le Cancer
• INRAE National Research Institute for Agriculture, Food and Environment

• ATF4
• ER stress
• IRE1a
• NFKBIZ
• inflammation
• miR-4734

• NFKBIZ
• ikappabZeta, IκBζ
• inflammation
• psoriasis

• Generalized pustular psoriasis
• autoinflammatory syndromes
• pathogenesis
• plaque psoriasis
• psoriasis vulgaris

• Acute Disease
• Humans
• Interleukin-17/therapeutic use
• Interleukins/genetics
• Keratinocytes/pathology
• Primary Immunodeficiency Diseases
• Psoriasis/drug therapy

Interleukin-17 (IL-17) family cytokines are potent drivers of inflammatory responses. Although IL-17 was originally identified as a cytokine that induces protective effects against bacterial and fungal infections, IL-17 can also promote chronic inflammation in a number of autoimmune diseases. Research in the last decade has also elucidated critical roles of IL-17 during cancer development and treatment. Intriguingly, IL-17 seems to play a role in the risk of cancers that are associated with metabolic disorders. In this review, we summarize our current knowledge on the biochemical basis of IL-17 signaling, IL-17′s involvement in cancers and metabolic disorders, and postulate how IL-17 family cytokines may serve as a bridge between these two types of diseases.

• Autoinflammation
• Early-phase psoriasis
• Gene
• Inflammatory skin disease
• Innate immune response

IκBζ is a transcriptional regulator that augments inflammatory responses from the Toll-like receptor or interleukin signaling. These innate immune responses contribute to the progression of nonalcoholic fatty liver disease (NAFLD); however, the role of IκBζ in the pathogenesis of NAFLD remains elusive. We investigated whether IκBζ was involved in the progression of NAFLD in mice. We generated hepatocyte-specific IκBζ-deficient mice (Alb-Cre; Nfkbiz^fl/fl) by crossing Nfkbiz^fl/fl mice with Alb-Cre transgenic mice. NAFLD was induced by feeding the mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). CDAHFD-induced IκBζ expression in the liver was observed in Nfkbiz^fl/fl mice, but not in Alb-Cre; Nfkbiz^fl/fl mice. Contrary to our initial expectation, IκBζ deletion in hepatocytes accelerated the progression of NAFLD after CDAHFD treatment. Although the increased expression of inflammatory cytokines and apoptosis-related proteins by CDAHFD remained unchanged between Nfkbiz^fl/fl and Alb-Cre; Nfkbiz^fl/fl mice, early-stage steatosis of the liver was significantly augmented in Alb-Cre; Nfkbiz^fl/fl mice. Overexpression of IκBζ in hepatocytes via the adeno-associated virus vector attenuated liver steatosis caused by the CDAHFD in wild-type C57BL/6 mice. This preventive effect of IκBζ overexpression on steatosis was not observed without transcriptional activity. Microarray analysis revealed a correlation between IκBζ expression and the changes of factors related to triglyceride biosynthesis and lipoprotein uptake. Our data suggest that hepatic IκBζ attenuates the progression of NAFLD possibly through the regulation of the factors related to triglyceride metabolism.

Elucidating transcriptome in the peripheral edge of the lesional (PE) skin could provide a better understanding of the molecules or signalings that intensify inflammation in the PE skin. Full-thickness biopsies of PE skin and uninvolved (UN) skin were obtained from psoriasis patients for RNA-seq. Several potential differentially expressed genes (DEGs) in the PE skin compared to those in the UN skin were identified. These DEGs enhanced functions such as angiogenesis, growth of epithelial tissue, chemotaxis and homing of cells, growth of connective tissues, and degranulation of myeloid cells beneath the PE skin. Moreover, the canonical pathways of IL-17A, IL-6, and IL-22 signaling were enriched by the DEGs. Finally, we proposed that inflammation in the PE skin might be driven by the IL-36/TLR9 axis or IL-6/Th17 axis and potentiated by IL-36α, IL-36γ, IL-17C, IL-8, S100A7, S100A8, S100A9, S100A15, SERPINB4, and hBD-2. Along with IL-36α, IL-17C, and IκBζ, ROCK2 could be an equally important factor in the pathogenesis of psoriasis, which may involve self-sustaining circuits between innate and adaptive immune responses via regulation of IL-36α and IL-36γ expression. Our finding provides new insight into signaling pathways in PE skin, which could lead to the discovery of new psoriasis targets.

• EGFR
• HB-EGF
• IL-17A
• IκBζ
• psoriasis signature gene

• NK cell
• autoimmunity
• immune tolerance
• inflammation
• innate lymphoid cell (ILC)
• tissue homeostasis
• tissue-resident immune cells

• Animals
• Homeostasis
• Immunity, Innate
• Inflammatory Bowel Diseases
• Lymphocytes
• Mice

• Canadian Institutes of Health Research
• Natural Sciences and Engineering Research Council of Canada

• ABT-317
• IKK-2 inhibitor IV
• IL-17A
• IL-22
• TNFα

Immune system is a complex network that clears pathogens, toxic substrates, and cancer cells. Distinguishing self-antigens from non-self-antigens is critical for the immune cell-mediated response against foreign antigens. The innate immune system elicits an early-phase response to various stimuli, whereas the adaptive immune response is tailored to previously encountered antigens. During immune responses, B cells differentiate into antibody-secreting cells, while naïve T cells differentiate into functionally specific effector cells [T helper 1 (Th1), Th2, Th17, and regulatory T cells]. However, enhanced or prolonged immune responses can result in autoimmune disorders, which are characterized by lymphocyte-mediated immune responses against self-antigens. Signal transduction of cytokines, which regulate the inflammatory cascades, is dependent on the members of the Janus family of protein kinases. Tyrosine kinase 2 (Tyk2) is associated with receptor subunits of immune-related cytokines, such as type I interferon, interleukin (IL)-6, IL-10, IL-12, and IL-23. Clinical studies on the therapeutic effects and the underlying mechanisms of Tyk2 inhibitors in autoimmune or chronic inflammatory diseases are currently ongoing. This review summarizes the findings of studies examining the role of Tyk2 in immune and/or inflammatory responses using Tyk2-deficient cells and mice.

• Tyrosine kinase 2
• Cytokines
• Signal transduction
• Immune system
• Inflammation

Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is itaconate, which is derived from cis-aconitate by the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on itaconate’s emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome. Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and inflammation.

• Animals
• Citric Acid Cycle/immunology
• Humans
• Inflammation/immunology
• Macrophage Activation
• Macrophages/immunology
• Succinates/immunology

• Lactobacillus reuteri
• Th17
• cutaneous microbiome
• fecal microbiota transplantation
• gut microbiota
• psoriasis

Psoriasis (PsO) is a common T cell-mediated inflammatory disorder of the skin with an estimated prevalence of 2%. The condition manifests most commonly as erythematous plaques covered with scales. The aetiology of PsO is multifactorial and disease initiation involves interactions between environmental factors, susceptibility genes, and innate and adaptive immune responses. The underlying pathology is mainly driven by interleukin-17. In addition, various inflammatory mediators from specific T helper (T_H) cell subsets, namely T_H1, T_H17, and T_H22, are overexpressed in cutaneous lesions and may also be detected in the peripheral blood of psoriatic patients. Moreover, these individuals are also at greater risk, compared to the general population, of developing multiple comorbid conditions. Cardiovascular disease (CVD) has been recognised as a prominent comorbidity of PsO. A potential mechanism contributing to this association may be the presence of a hypercoagulable state in these individuals. Inflammation and coagulation are closely related. The presence of chronic, low-grade systemic inflammation may promote thrombosis – one of the major determinants of CVD. A pro-inflammatory milieu may induce the expression of tissue factor, augment platelet activity, and perturb the vascular endothelium. Altogether, these changes will result in a prothrombotic state. In this review, we describe the aetiology of PsO, as well as the pathophysiology of the condition. We also consider its relationship to CVD. Given the systemic inflammatory nature of PsO, we evaluate the potential contribution of prominent inflammatory mediators (implicated in PsO pathogenesis) to establishing a prothrombotic state in psoriatic patients.

• cardiovascular disease
• endothelium
• hypercoagulability
• platelets
• psoriasis
• systemic inflammation

This study aims to determine a role of interleukin‐17A (IL‐17) in salivary gland (SG) dysfunction and therapeutic effects of targeting IL‐17 in SG for treating autoimmune sialadenitis in primary Sjögren’s syndrome (pSS).

Salivary IL‐17 levels and IL‐17‐secreting cells in labial glands of pSS patients were examined. Kinetic changes of IL‐17‐producing cells in SG from mice with experimental Sjögren’s syndrome (ESS) were analysed. To determine a role of IL‐17 in salivary secretion, IL‐17‐deficient mice and constructed chimeric mice with IL‐17 receptor C (IL‐17RC) deficiency in non‐hematopoietic and hematopoietic cells were examined for saliva flow rates during ESS development. Both human and murine primary SG epithelial cells were treated with IL‐17 for measuring cholinergic activation‐induced calcium movement. Moreover, SG functions were assessed in ESS mice with salivary retrograde cannulation of IL‐17 neutralisation antibodies.

Increased salivary IL‐17 levels were negatively correlated with saliva flow rates in pSS patients. Both IL‐17‐deficient mice and chimeric mice with non‐hematopoietic cell‐restricted IL‐17RC deficiency exhibited no obvious salivary reduction while chimeric mice with hematopoietic cell‐restricted IL‐17RC deficiency showed significantly decreased saliva secretion during ESS development. In SG epithelial cells, IL‐17 inhibited acetylcholine‐induced calcium movement and downregulated the expression of transient receptor potential canonical 1 via promoting Nfkbiz mRNA stabilisation. Moreover, local IL‐17 neutralisation in SG markedly attenuated hyposalivation and ameliorated tissue inflammation in ESS mice.

These findings identify a novel function of IL‐17 in driving salivary dysfunction during pSS development and may provide a new therapeutic strategy for targeting SG dysfunction in pSS patients.

• IL‐17
• autoimmune sialadenitis
• calcium movement
• primary Sjögren’s syndrome
• salivary dysfunction

• Curcuma amada
• Humulus lupulus
• Hypericum perforatum
• inflammation
• interleukin 17A
• interleukin 22
• psoriasis
• β-defensin 2

• Biomarker
• IL-17
• Spondyloarthritis
• pathogenesis
• treatment

• Psoriasis
• bioinformatic approaches
• differentially expressed genes
• hub gene
• network analysis
• pathogenesis

Antimicrobial peptides (AMPs) are small molecules produced by a myriad of cells and play important roles not only in protecting against infections and sustaining skin barrier homeostasis but also in contributing to immune dysregulation under pathological conditions. Recently, increasing evidence has indicated that AMPs, including cathelicidin (LL-37), human β-defensins, S100 proteins, lipocalin 2, and RNase 7, are highly expressed in psoriatic skin lesions. These peptides broadly regulate immunity by interacting with various immune cells and linking innate and adaptive immune responses during the progression of psoriasis. In this review, we summarize the recent findings regarding AMPs in the pathogenesis of psoriasis with a main focus on their immunomodulatory abilities.

Psoriasis is an immune-mediated inflammatory skin disease with a complex etiology involving environmental and genetic factors. A better insight into related genomic alteration helps design precise therapies leading to better treatment outcome. Gene expression in psoriasis can provide relevant information about the altered expression of mRNA transcripts, thus giving new insights into the disease onset. Techniques for transcriptome analyses, such as microarray and RNA sequencing (RNA-seq), are relevant tools for the discovery of new biomarkers as well as new therapeutic targets. This review summarizes the findings related to the contribution of keratinocytes in the pathogenesis of psoriasis by an in-depth review of studies that have examined psoriatic transcriptomes in the past years. It also provides valuable information on reconstructed 3D psoriatic skin models using cells isolated from psoriatic patients for transcriptomic studies.

• RNA-seq
• gene expression
• keratinocytes
• microarray
• psoriasis
• skin
• transcriptome

Baicalin is a flavone isolated from the root of Scutellaria baicalensis and is used in traditional Chinese medicine. Psoriasis is a persistent and recurrent chronic inflammatory skin disease that is characterized by inflammation and increased proliferation of keratinocytes. This study aimed to investigate the effects of baicalin on HaCaT immortalized human keratinocytes in vitro and the molecular mechanisms involved.

HaCaT keratinocytes were cultured in increasing concentrations of baicalin at 6.25 μM, 12.5 μM, and 25 μM. The in vitro model of psoriasis was established using HaCaT cells treated with tumor necrosis factor-α (TNF-α). The MTT assay was used to asses cell viability and apoptosis. Western blot was used to measure the expression of Bcl-2, Bax, pro-caspase-3, and cleaved caspase-3, and enzyme-linked immunosorbent assay (ELISA) was performed to detect inflammatory cytokines. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the levels of STAT3 and p65 mRNA.

Baicalin reduced cell viability and induced apoptosis of HaCaT human keratinocytes in a dose-dependent manner. Increased cell viability and the expression of inflammatory cytokines by HaCaT cells induced by TNF-α were significantly inhibited by baicalin. Baicalin significantly inhibited the activation of the STAT3/NF-κB pathway in HaCaT cells stimulated by TNF-α.

Baicalin inhibited the proliferation and expression of inflammatory cytokines in HaCaT immortalized human keratinocytes in vitro through the inhibition of the STAT3/NF-κB signaling pathway.

The molecular basis of interleukin (IL)‐17A in driving psoriasis pathogenesis is not fully elucidated yet. To investigate the underlying mechanisms and biomarkers associated with IL‐17A and the role in psoriasis pathogenesis, over 30 serum proteins were evaluated in a study assessing the effectiveness and safety of secukinumab, where treatment was directly switched from cyclosporin A to secukinumab. Serum β‐defensin 2 (BD‐2) levels rapidly and robustly reduced following secukinumab treatment. BD‐2 levels were well‐correlated with Psoriasis Area and Severity Index (PASI) score; changes in BD‐2 levels preceded change in PASI score. Serum BD‐2, an easily measurable protein, can possibly be used as a suitable surrogate biomarker to monitor responses to IL‐17A‐targeted therapies for psoriasis in clinical practice.

• biomarker
• interleukin-17A
• psoriasis
• secukinumab
• β-defensin 2

• RNA-seq
• inflammation
• regulation
• time series
• transcription

The excellent clinical efficacy of anti-interleukin 17A (IL-17A) biologics on psoriasis indicates a crucial pathogenic role of IL-17A in this autoinflammatory skin disease. IL-17A accelerates the proliferation of epidermal keratinocytes. Keratinocytes produce a myriad of antimicrobial peptides and chemokines, such as CXCL1, CXCL2, CXCL8, and CCL20. Antimicrobial peptides enhance skin inflammation. IL-17A is capable of upregulating the production of these chemokines and antimicrobial peptides in keratinocytes. CXCL1, CXCL2, and CXCL8 recruit neutrophils and CCL20 chemoattracts IL-17A-producing CCR6⁺ immune cells, which further contributes to forming an IL-17A-rich milieu. This feed-forward pathogenic process results in characteristic histopathological features, such as epidermal hyperproliferation, intraepidermal neutrophilic microabscess, and dermal CCR6⁺ cell infiltration. In this review, we focus on IL-17A and keratinocyte interaction regarding psoriasis pathogenesis.

• CCL20
• CXCL1
• CXCL8
• ILC3
• Koebner phenomenon
• Th17
• antimicrobial peptides
• interleukin-17A
• keratinocytes
• psoriasis

During the last decades, high-throughput assessment of gene expression in patient tissues using microarray technology or RNA-Seq took center stage in clinical research. Insights into the diversity and frequency of transcripts in healthy and diseased conditions provide valuable information on the cellular status in the respective tissues. Growing with the technique, the bioinformatic analysis toolkit reveals biologically relevant pathways which assist in understanding basic pathophysiological mechanisms. Conventional classification systems of inflammatory skin diseases rely on descriptive assessments by pathologists. In contrast to this, molecular profiling may uncover previously unknown disease classifying features. Thereby, treatments and prognostics of patients may be improved. Furthermore, disease models in basic research in comparison to the human disease can be directly validated. The aim of this article is not only to provide the reader with information on the opportunities of these techniques, but to outline potential pitfalls and technical limitations as well. Major published findings are briefly discussed to provide a broad overview on the current findings in transcriptomics in inflammatory skin diseases.

• RNA-Seq
• acne
• atopic dermatitis
• contact dermatitis
• eczema
• inflammatory skin diseases
• microarray
• psoriasis
• scRNA-Seq
• transcriptomics

• Acitretin
• GPP
• IL-36
• IκBζ
• Psoriasis

The transcriptional activator IκBζ is a key regulator of psoriasis, but which cells mediate its pathogenic effect remains unknown. Here we found that IκBζ expression in keratinocytes triggers not only skin lesions but also systemic inflammation in mouse psoriasis models. Specific depletion of IκBζ in keratinocytes was sufficient to suppress the induction of imiquimod- or IL-36–mediated psoriasis. Moreover, IκBζ ablation in keratinocytes prevented the onset of psoriatic lesions and systemic inflammation in keratinocyte-specific IL-17A–transgenic mice. Mechanistically, this psoriasis protection was mediated by IκBζ deficiency in keratinocytes abrogating the induction of specific proinflammatory target genes, including Cxcl5, Cxcl2, Csf2, and Csf3, in response to IL-17A or IL-36. These IκBζ-dependent genes trigger the generation and recruitment of neutrophils and monocytes that are needed for skin inflammation. Consequently, our data uncover a surprisingly pivotal role of keratinocytes and keratinocyte-derived IκBζ as key mediators of psoriasis and psoriasis-related systemic inflammation.

Deletion of IκBζ in keratinocytes is sufficient to abrogate psoriasis induction in mouse models due to changes in transcription of keratinocyte-derived chemo- and cytokines.

• Autoimmune diseases
• Autoimmunity
• Dermatology
• Innate immunity
• Skin

• Adaptor Proteins, Signal Transducing/genetics
• Adult
• Arthritis, Psoriatic/genetics
• Arthritis, Psoriatic/metabolism
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease/genetics
• Genotype
• Humans
• Logistic Models
• Male
• Middle Aged
• NF-KappaB Inhibitor alpha/metabolism
• NF-kappa B/metabolism
• NF-kappa B p50 Subunit/genetics
• Polymorphism, Single Nucleotide
• Psoriasis/genetics
• Risk Factors
• Spain

Immunomodulation with anti‐TNF‐α is highly effective in the treatment of various immune‐mediated inflammatory diseases, including hidradenitis suppurativa (HS). However, this may be responsible for unexpected paradoxical psoriasiform reactions. The pathogenic mechanisms underlying the induction of these events are not clear, even though the involvement of innate immune responses driven by plasmacytoid dendritic cells (pDC) has been described. In addition, the genetic predisposition to psoriasis of patients could be determinant. In this study, we investigated the immunological and genetic profiles of three HS patients without psoriasis who developed paradoxical psoriasiform reactions following anti‐TNF‐α therapy with adalimumab. We found that paradoxical psoriasiform skin reactions show immunological features common to the early phases of psoriasis development, characterized by cellular players of innate immunity, such as pDC, neutrophils, mast cells, macrophages, and monocytes. In addition, IFN‐β and IFN‐α2a, two type I IFNs typical of early psoriasis, were highly expressed in paradoxical skin reactions. Concomitantly, other innate immunity molecules, such as the catheledicin LL37 and lymphotoxin (LT)‐α and LT‐β were overproduced. Interestingly, these innate immunity molecules were abundantly expressed by keratinocytes, in addition to the inflammatory infiltrate. In contrast to classical psoriasis, psoriasiform lesions of HS patients showed a reduced number of IFN‐γ and TNF‐α‐releasing T lymphocytes. On the contrary, IL‐22 immunoreactivity was significantly augmented together with the IL‐36γ staining in leukocytes infiltrating the dermis. Finally, we found that all HS patients with paradoxical reactions carried allelic variants in genes predisposing to psoriasis. Among them, SNPs in ERAP1, NFKBIZ, and TNFAIP genes and in the HLA‐C genomic region were found.

• anti-TNF-α therapy
• hidradenitis suppurativa
• innate immunity
• lymphotoxin
• paradoxical psoriasis
• psoriasis
• skin inflammation
• type I IFN

• IL-17A
• IκBζ
• NF-κB activator 1
• NFKBIZ
• Secukinumab
• c-Jun
• keratinocytes
• nuclear factor κB
• p38 mitogen-activated protein kinase
• psoriasis

• Atherosclerosis
• Coronary artery disease
• Gene polymorphisms
• Genetic association
• NF-KB pathway

• Adaptive immunity
• IL-17 receptor A
• IL-17A
• IL-17F
• Innate immunity
• Psoriasis

• Adaptive Immunity
• Arthritis, Psoriatic/diagnosis
• Arthritis, Psoriatic/etiology
• Arthritis, Psoriatic/metabolism
• Cytokines/metabolism
• Disease Susceptibility
• Humans
• Immunity, Innate
• Inflammation Mediators/metabolism
• Interleukin-17/immunology
• Interleukin-17/metabolism
• Psoriasis/diagnosis
• Psoriasis/etiology
• Psoriasis/metabolism
• Receptors, Interleukin-17/metabolism
• Th17 Cells/immunology
• Th17 Cells/metabolism

• 3' Untranslated Regions
• Adaptor Proteins, Signal Transducing/metabolism
• Animals
• CCAAT-Enhancer-Binding Protein-beta/metabolism
• Cytokines/metabolism
• DNA-Binding Proteins/metabolism
• Fibroblasts/metabolism
• HEK293 Cells
• Humans
• Inflammation
• Interleukin-17/metabolism
• Keratinocytes/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nuclear Proteins/metabolism
• Protein Binding
• RNA, Messenger/metabolism
• RNA-Binding Proteins/metabolism
• Ribonucleases/metabolism
• Signal Transduction
• TNF Receptor-Associated Factor 2/metabolism
• Transcription Factors/metabolism

• R37 DE022550 NIDCR NIH HHS
• R01 AI130025 NIAID NIH HHS
• R01 DE023815 NIDCR NIH HHS
• R01 AI080870 NIAID NIH HHS
• R01 GM116889 NIGMS NIH HHS
• R01 AI107825 NIAID NIH HHS
• P30 AR075043 NIAMS NIH HHS
• R21 AI128991 NIAID NIH HHS
• R01 AR069071 NIAMS NIH HHS

Psoriasis is an autoinflammatory disease characterized by cytokine-driven keratinocyte proliferation and infiltration of immune cells. While IL-17A and TNFα are established targets in psoriasis therapy, IL-36 is emerging as an important cytokine in this disease. The mechanisms of IL-36–driven proinflammatory responses are largely unknown. Here we identified IκBζ, a transcriptional regulator of selective NF-κB target genes, as a crucial mediator of IL-36 action. In keratinocytes, IκBζ was required for the expression of several psoriasis-related cytokines and chemokines. Moreover, genetic deletion of IκBζ prevented IL-36–mediated dermatitis induction in mice. Since IκBζ is essential not only for IL-36 but also for IL-17 signaling, our results suggest that inhibition of IκBζ function could be a future strategy in psoriasis therapy.

Proinflammatory cytokine signaling in keratinocytes plays a crucial role in the pathogenesis of psoriasis, a skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although IL-17A and TNFα are effective therapeutic targets in psoriasis, IL-36 has recently emerged as a proinflammatory cytokine. However, little is known about IL-36 signaling and its downstream transcriptional responses. Here, we found that exposure of keratinocytes to IL-36 induced the expression of IκBζ, an atypical IκB member and a specific transcriptional regulator of selective NF-κB target genes. Induction of IκBζ by IL-36 was mediated by NF-κB and STAT3. In agreement, IL-36–mediated induction of IκBζ was found to be required for the expression of various psoriasis-related genes involved in inflammatory signaling, neutrophil chemotaxis, and leukocyte activation. Importantly, IκBζ-knockout mice were protected against IL-36–mediated dermatitis, accompanied by reduced proinflammatory gene expression, decreased immune cell infiltration, and a lack of keratinocyte hyperproliferation. Moreover, expression of IκBζ mRNA was highly up-regulated in biopsies of psoriasis patients where it coincided with IL36G levels. Thus our results uncover an important role for IκBζ in IL-36 signaling and validate IκBζ as an attractive target for psoriasis therapy.

• IL-36
• IκBζ
• NFKBIZ
• keratinocytes
• psoriasis

Psoriasis is a chronic inflammatory skin disease resulting from genetic, epigenetic, environmental, and lifestyle factors. To date, several immunopathogenic mechanisms of psoriasis have been elucidated, and, in the current model, the cross talk between autoreactive T cells and resident keratinocytes generates inflammatory and immune circuits responsible for the initiation, progression, and persistence of the disease. Several autoantigens derived from keratinocytes (i.e., LL37 cathelecidin/nucleic acid complexes, newly generated lipid antigens) have been identified, which may trigger initial activation of T cells, particularly IL-17-producing T cells, T helper (Th)1 and Th22 cells. Hence, lymphokines released in skin lesions are pivotal for keratinocyte activation and production of inflammatory molecules, which in turn lead to amplification of the local immune responses. Intrinsic genetic alterations of keratinocytes in the activation of signal transduction pathways dependent on T-cell-derived cytokines are also fundamental. The current review emphasizes the aberrant interplay of immune cells and skin-resident keratinocytes in establishing and sustaining inflammatory and immune responses in psoriasis.

• adaptive immunity
• immune cells
• innate immunity
• keratinocytes
• psoriasis
• skin inflammation