RESUMO
Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.
Assuntos
Microambiente Celular/imunologia , Células Dendríticas/imunologia , Imunidade Inata , Mitocôndrias/imunologia , Espécies Reativas de Oxigênio/imunologia , Resposta a Proteínas não Dobradas/imunologia , Animais , Microambiente Celular/genética , Ciclo do Ácido Cítrico/genética , Ciclo do Ácido Cítrico/imunologia , Células Dendríticas/patologia , Hexoquinase/genética , Hexoquinase/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Resposta a Proteínas não Dobradas/genética , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/imunologiaRESUMO
Cytosolic innate immune sensing is critical for protecting barrier tissues. NOD1 and NOD2 are cytosolic sensors of small peptidoglycan fragments (muropeptides) derived from the bacterial cell wall. These muropeptides enter cells, especially epithelial cells, through unclear mechanisms. We previously implicated SLC46 transporters in muropeptide transport in Drosophila immunity. Here, we focused on Slc46a2, which was highly expressed in mammalian epidermal keratinocytes, and showed that it was critical for the delivery of diaminopimelic acid (DAP)-muropeptides and activation of NOD1 in keratinocytes, whereas the related transporter Slc46a3 was critical for delivering the NOD2 ligand MDP to keratinocytes. In a mouse model, Slc46a2 and Nod1 deficiency strongly suppressed psoriatic inflammation, whereas methotrexate, a commonly used psoriasis therapeutic, inhibited Slc46a2-dependent transport of DAP-muropeptides. Collectively, these studies define SLC46A2 as a transporter of NOD1-activating muropeptides, with critical roles in the skin barrier, and identify this transporter as an important target for anti-inflammatory intervention.
Assuntos
Dermatite , Metotrexato , Camundongos , Animais , Metotrexato/farmacologia , Inflamação , Peptidoglicano/metabolismo , Células Epiteliais/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Imunidade Inata , MamíferosRESUMO
Dietary components and metabolites have a profound impact on immunity and inflammation. Here, we investigated how sensing of cholesterol metabolite oxysterols by γδ T cells impacts their tissue residency and function. We show that dermal IL-17-producing γδ T (Tγδ17) cells essential for skin-barrier homeostasis require oxysterols sensing through G protein receptor 183 (GPR183) for their development and inflammatory responses. Single-cell transcriptomics and murine reporter strains revealed that GPR183 on developing γδ thymocytes is needed for their maturation by sensing medullary thymic epithelial-cell-derived oxysterols. In the skin, basal keratinocytes expressing the oxysterol enzyme cholesterol 25-hydroxylase (CH25H) maintain dermal Tγδ17 cells. Diet-driven increases in oxysterols exacerbate Tγδ17-cell-mediated psoriatic inflammation, dependent on GPR183 on γδ T cells. Hence, cholesterol-derived oxysterols control spatially distinct but biologically linked processes of thymic education and peripheral function of dermal T cells, implicating diet as a focal parameter of dermal Tγδ17 cells.
Assuntos
Colesterol na Dieta , Oxisteróis , Humanos , Animais , Camundongos , Oxisteróis/metabolismo , Pele/metabolismo , Inflamação , Proteínas de Ligação ao GTP/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Obesity is a major risk factor for psoriasis, but how obesity disrupts the regulatory mechanisms that keep skin inflammation in check is unclear. Here, we found that skin was enriched with a unique population of CD4+Foxp3+ regulatory T (Treg) cells expressing the nuclear receptor peroxisome proliferation-activated receptor gamma (PPARγ). PPARγ drove a distinctive transcriptional program and functional suppression of IL-17A+ γδ T cell-mediated psoriatic inflammation. Diet-induced obesity, however, resulted in a reduction of PPARγ+ skin Treg cells and a corresponding loss of control over IL-17A+ γδ T cell-mediated inflammation. Mechanistically, PPARγ+ skin Treg cells preferentially took up elevated levels of long-chain free fatty acids in obese mice, which led to cellular lipotoxicity, oxidative stress, and mitochondrial dysfunction. Harnessing the anti-inflammatory properties of these PPARγ+ skin Treg cells could have therapeutic potential for obesity-associated inflammatory skin diseases.
Assuntos
Psoríase , Linfócitos T Reguladores , Animais , Camundongos , PPAR gama , Interleucina-17 , Pele , Psoríase/induzido quimicamente , Inflamação , ObesidadeRESUMO
iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signaling; they function primarily by recognizing transmembrane domains of their clients. Here, we report a mechanistically distinct nuclear function of iRhoms, showing that both human and mouse iRhom2 are non-canonical substrates of signal peptidase complex (SPC), the protease that removes signal peptides from secreted proteins. Cleavage of iRhom2 generates an N-terminal fragment that enters the nucleus and modifies the transcriptome, in part by binding C-terminal binding proteins (CtBPs). The biological significance of nuclear iRhom2 is indicated by elevated levels in skin biopsies of patients with psoriasis, tylosis with oesophageal cancer (TOC), and non-epidermolytic palmoplantar keratoderma (NEPPK); increased iRhom2 cleavage in a keratinocyte model of psoriasis; and nuclear iRhom2 promoting proliferation of keratinocytes. Overall, this work identifies an unexpected SPC-dependent ER-to-nucleus signaling pathway and demonstrates that iRhoms can mediate nuclear signaling.
Assuntos
Psoríase , Transdução de Sinais , Animais , Humanos , Camundongos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Psoríase/genética , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismoRESUMO
High-throughput single-cell RNA-sequencing (scRNA-seq) methodologies enable characterization of complex biological samples by increasing the number of cells that can be profiled contemporaneously. Nevertheless, these approaches recover less information per cell than low-throughput strategies. To accurately report the expression of key phenotypic features of cells, scRNA-seq platforms are needed that are both high fidelity and high throughput. To address this need, we created Seq-Well S3 ("Second-Strand Synthesis"), a massively parallel scRNA-seq protocol that uses a randomly primed second-strand synthesis to recover complementary DNA (cDNA) molecules that were successfully reverse transcribed but to which a second oligonucleotide handle, necessary for subsequent whole transcriptome amplification, was not appended due to inefficient template switching. Seq-Well S3 increased the efficiency of transcript capture and gene detection compared with that of previous iterations by up to 10- and 5-fold, respectively. We used Seq-Well S3 to chart the transcriptional landscape of five human inflammatory skin diseases, thus providing a resource for the further study of human skin inflammation.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Inflamação/genética , RNA Citoplasmático Pequeno/genética , Pele/patologia , Animais , Linhagem Celular , DNA Complementar/genética , Células HEK293 , Humanos , Camundongos , Células NIH 3T3 , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Transcrição Gênica/genética , Transcriptoma/genéticaRESUMO
Psoriasis is a chronic inflammatory disease whose etiology is multifactorial. The contributions of cellular metabolism to psoriasis are unclear. Here, we report that interleukin-17 (IL-17) downregulated Protein Phosphatase 6 (PP6) in psoriatic keratinocytes, causing phosphorylation and activation of the transcription factor C/EBP-ß and subsequent generation of arginase-1. Mice lacking Pp6 in keratinocytes were predisposed to psoriasis-like skin inflammation. Accumulation of arginase-1 in Pp6-deficient keratinocytes drove polyamine production from the urea cycle. Polyamines protected self-RNA released by psoriatic keratinocytes from degradation and facilitated the endocytosis of self-RNA by myeloid dendritic cells to promote toll-like receptor-7 (TLR7)-dependent RNA sensing and IL-6 production. An arginase inhibitor improved skin inflammation in murine and non-human primate models of psoriasis. Our findings suggest that urea cycle hyperreactivity and excessive polyamine generation in psoriatic keratinocytes promote self-RNA sensation and PP6 deregulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis.
Assuntos
Células Dendríticas/imunologia , Queratinócitos/metabolismo , Fosfoproteínas Fosfatases/deficiência , Poliaminas/metabolismo , Psoríase/patologia , RNA/imunologia , Células 3T3 , Animais , Arginase/antagonistas & inibidores , Arginase/metabolismo , Arginina/metabolismo , Autoantígenos/imunologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Células HEK293 , Células HaCaT , Humanos , Interleucina-17/metabolismo , Macaca fascicularis , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fosfoproteínas Fosfatases/genética , Fosforilação , Pele/patologia , Receptor 7 Toll-Like/imunologiaRESUMO
Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.
Assuntos
Ácido Láctico , Psoríase , Camundongos , Animais , Ácido Láctico/metabolismo , Ácido Láctico/farmacologia , Pele/metabolismo , Macrófagos/metabolismo , Inflamação/metabolismo , Psoríase/metabolismoRESUMO
Psoriasis is a chronic autoinflammatory skin disease. Although interleukin-17, derived from lymphocytes, has been shown to be critical in psoriasis, the initiation and maintenance of chronic skin inflammation has not been well understood. IL-25 (also called IL-17E), another IL-17 family cytokine, is well known to regulate allergic responses and type 2 immunity. Here we have shown that IL-25, also highly expressed in the lesional skin of psoriasis patients, was regulated by IL-17 in murine skin of a imiquimod (IMQ)-induced psoriasis model. IL-25 injection induced skin inflammation, whereas germline or keratinocyte-specific deletion of IL-25 caused resistance to IMQ-induced psoriasis. Via IL-17RB expression in keratinocytes, IL-25 stimulated the proliferation of keratinocytes and induced the production of inflammatory cytokines and chemokines, via activation of the STAT3 transcription factor. Thus, our data demonstrate that an IL-17-induced autoregulatory circuit in keratinocytes is mediated by IL-25 and suggest that this circuit could be targeted in the treatment of psoriasis patients.
Assuntos
Interleucina-17/imunologia , Psoríase/imunologia , Receptores de Interleucina-17/imunologia , Receptores de Interleucina/imunologia , Fator de Transcrição STAT3/metabolismo , Pele/patologia , Animais , Linhagem Celular , Proliferação de Células , Ativação Enzimática , Células HEK293 , Humanos , Imiquimode/toxicidade , Inflamação/imunologia , Inflamação/patologia , Interleucina-17/genética , Queratinócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Psoríase/induzido quimicamente , Psoríase/patologia , Pele/imunologiaRESUMO
Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rß1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.
Assuntos
Subunidade beta 1 de Receptor de Interleucina-12/metabolismo , Interleucina-23/metabolismo , Receptores de Interleucina/metabolismo , Animais , Calorimetria/métodos , Linhagem Celular , Humanos , Interferometria/métodos , Subunidade p40 da Interleucina-12/metabolismo , Masculino , Camundongos , Ligação Proteica/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid-derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases. These lipid mediators act not only through signaling by themselves but also by potentiating the signaling of other chemical mediators, such as cytokines and chemokines. For instance, prostaglandin E2 -EP4 and LTB4 -BLT1 signaling on cutaneous dendritic cells substantially facilitate their chemokine-induced migration ability into the skin and play critical roles in the priming and/or activation of antigen-specific effector T cells in the skin. In addition to these ω6 fatty acid-derived metabolites, various ω3 fatty acid-derived metabolites regulate skin immune cell functions, and some exert potent anti-inflammatory functions. Lipid mediators act as modulators of cutaneous immune responses, and manipulating the signaling from lipid mediators has the potential as a novel therapeutic approach for human skin diseases.
Assuntos
Dermatite Atópica , Dermatopatias , Humanos , Animais , Camundongos , Prostaglandinas , Pele , Ácidos GraxosRESUMO
Tissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8+ Trm cells on a compartmental and functional basis. In human skin epithelia, CD8+CD49a+ Trm cells produced interferon-γ, whereas CD8+CD49a- Trm cells produced interleukin-17 (IL-17). In addition, CD8+CD49a+ Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8+CD49a+ Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8+CD49a- Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8+ Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica/imunologia , Integrina alfa1/imunologia , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Separação Celular , Citometria de Fluxo , Humanos , Memória Imunológica/imunologia , Integrina alfa1/biossíntese , Ativação Linfocitária/imunologia , Microscopia Confocal , Psoríase/imunologia , Vitiligo/imunologiaRESUMO
Izumo1R is a pseudo-folate receptor with an essential role in mediating tight oocyte/spermatozoa contacts during fertilization. Intriguingly, it is also expressed in CD4+ T lymphocytes, in particular Treg cells under the control of Foxp3. To understand Izumo1R function in Treg cells, we analyzed mice with Treg-specific Izumo1r deficiency (Iz1rTrKO). Treg differentiation and homeostasis were largely normal, with no overt autoimmunity and only marginal increases in PD1+ and CD44hi Treg phenotypes. pTreg differentiation was also unaffected. Iz1rTrKO mice proved uniquely susceptible to imiquimod-induced, γδT cell-dependent, skin disease, contrasting with normal responses to several inflammatory or tumor challenges, including other models of skin inflammation. Analysis of Iz1rTrKO skin revealed a subclinical inflammation that presaged IMQ-induced changes, with an imbalance of Rorγ+ γδT cells. Immunostaining of normal mouse skin revealed the expression of Izumo1, the ligand for Izumo1R, electively in dermal γδT cells. We propose that Izumo1R on Tregs enables tight contacts with γδT cells, thereby controlling a particular path of skin inflammation.
Assuntos
Dermatite , Psoríase , Receptores de Superfície Celular , Dermatopatias , Linfócitos T Reguladores , Animais , Camundongos , Dermatite/metabolismo , Imiquimode , Inflamação/metabolismo , Psoríase/metabolismo , Receptores de Superfície Celular/metabolismo , Pele/metabolismo , Dermatopatias/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
Although biologics have achieved tremendous success in the treatment of psoriasis and revolutionized the clinical management of the disease, certain issues arise during treatments, including the phenotypic switch from psoriasis to other skin disorders and the recurrence of psoriasis after the cessation of biologic treatment. Here we provide a concise overview of the roles of keratinocytes in the pathogenesis of psoriasis, elucidate the involvement of keratinocytes in the phenotypic switch and relapse of psoriasis, and address the challenges encountered in both basic and clinical research on psoriasis.
Assuntos
Queratinócitos , Fenótipo , Psoríase , Recidiva , Psoríase/imunologia , Psoríase/patologia , Humanos , Queratinócitos/imunologia , AnimaisRESUMO
In COVID-19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre-existing autoimmune conditions can therefore be at increased risk of severe COVID-19 and/or associated sequelae, yet SARS-CoV-2 infection in this group has been little studied. Here, we performed single-cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS-CoV-2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell-cell communication that substantially shape the immune response under SARS-CoV-2 infection. While enrichment of HLA-DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type-I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS-CoV-2 in patients with pre-existing autoimmunity, highlighting important considerations for disease treatment and follow-up.
Assuntos
Doenças Autoimunes , COVID-19 , Humanos , SARS-CoV-2 , Leucócitos Mononucleares , Multiômica , Autoimunidade , Análise de Célula ÚnicaRESUMO
Langerhans cells (LCs) are the key antigen-presenting cells in the epidermis in normal conditions and respond differentially to environmental and/or endogenous stimuli, exerting either proinflammatory or anti-inflammatory effects. Current knowledge about LCs mainly originates from studies utilizing mouse models, whereas with the development of single-cell techniques, there has been significant progress for human LCs, which has updated our understanding of the phenotype, ontogeny, differentiation regulation, and function of LCs. In this review, we delineated the progress of human LCs and summarized LCs' function in inflammatory skin diseases, providing new ideas for precise regulation of LC function in the prevention and treatment of skin diseases.
RESUMO
Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insults, such as infection, and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in the thymus, and develop only subtle immune-mediated pathology in the steady state. However, we found that transient lymphopenia induced by total body irradiation (TBI) or cyclophosphamide (CY) results in massive dermatitis in Dsg3H1 mice. The symptoms included expansion and development of self-reactive T cells, their differentiation into CD44high IL-17-producing helper T cells, and severe neutrophilic inflammation. Repopulation of FOXP3+ T regulatory cells after lymphopenia normally occurred, suggesting escape of skin-reactive conventional T cells from control by regulatory T cells. Furthermore, we found that a depletion of the intestinal microbiota by antibiotics prevents CY-induced dermatitis, indicating roles of the commensal intestinal microbiota in LIP and Th17 development in vivo. The current data suggested that post-thymic tolerance of Dsg3H1 mice is established on a fragile balance in the lymphoreplete immune environment and broken by the interplay between lymphopenia and intestinal microbiota. The dynamic phenotypes observed in Dsg3H1 mice prompt a re-evaluation of opportunistic lymphopenia together with the microbiota as pivotal environmental factors, impacting individuals with genetic predispositions for autoimmune diseases.
Assuntos
Microbioma Gastrointestinal , Tolerância Imunológica , Linfopenia , Camundongos Transgênicos , Animais , Camundongos , Microbioma Gastrointestinal/imunologia , Linfopenia/imunologia , Tolerância Imunológica/imunologia , Pele/imunologia , Pele/microbiologia , Pele/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Timo/imunologia , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Elevated IL-21 expression which can effectively induce Th17 cell differentiation has been implicated in the pathogenesis of psoriasis, but its role in angiogenesis remains poorly understood. METHODS: PASI and PSI score assessment was applied to evaluate the severity of psoriatic lesions. The expression of IL-21, IL-21 receptor (IL-21R), CD31, VEGFA, MMP-9, and ICAM-1 in skin was determined by immunohistochemistry or quantitative real-time polymerase chain reaction. The serum level of IL-21 was measured by enzyme-linked immunosorbent assay (ELISA). Then, their correlation was analyzed statistically. Human umbilical vein endothelial cells (HUVECs) cocultured with conditional medium from normal human epidermal keratinocytes (NHEKs) were treated with IL-21 and/or M5 cocktail (mixture of IL-1α, IL-17A, IL-22, TNF-α, and oncostatin M). The migration and tube formation of HUVECs were detected, and the levels of VEGFA, MMP-9, and ICAM-1 in NHEKs were measured by Western blotting or ELISA. RESULTS: Increased IL-21 and IL-21R expression was observed in psoriatic sera or skin specimens, with IL-21R mainly locating in keratinocytes and IL-21 in immune cells. Pearson analysis showed significantly positive correlation between IL-21/IL-21R and erythema scores/microvessel density in psoriatic lesions. Moreover, the expression of proangiogenic genes, VEGFA, ICAM-1, and MMP-9 was upregulated in skins of psoriasis. Additionally, in M5 microenvironment, migration and tube formation could be magnified in HUVECs using IL-21 pre-treated NHEK medium. Mechanically, the co-stimulation of IL-21 and M5 to NEHKs increased the expression of ICAM-1. CONCLUSION: IL-21 could regulate keratinocytes to secrete ICAM-1, thereby promoting angiogenesis in psoriasis.
Assuntos
Interleucinas , Psoríase , Humanos , Angiogênese , Células Endoteliais/metabolismo , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Queratinócitos/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Psoríase/metabolismo , Pele/metabolismo , Interleucinas/metabolismoRESUMO
Inflammation resolution is an essential process for preventing the development of chronic inflammatory diseases. However, the mechanisms that regulate inflammation resolution in psoriasis are not well understood. Here, we report that ANKRD22 is an endogenous negative orchestrator of psoriasiform inflammation because ANKRD22-deficient mice are more susceptible to IMQ-induced psoriasiform inflammation. Mechanistically, ANKRD22 deficiency leads to excessive activation of the TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, resulting in the hyperproduction of IL-23 in DCs. This is due to ANKRD22 being a negative feedback regulator for NIK because it physically binds to and assists in the degradation of accumulated NIK. Clinically, ANKRD22 is negatively associated with IL-23A expression and psoriasis severity. Of greater significance, subcutaneous administration of an AAV carrying ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Our findings suggest ANKRD22, an endogenous supervisor of NIK, is responsible for inflammation resolution in psoriasis, and may be explored in the context of psoriasis therapy.
Assuntos
Modelos Animais de Doenças , Interleucina-23 , Psoríase , Transdução de Sinais , Psoríase/metabolismo , Psoríase/patologia , Psoríase/terapia , Psoríase/etiologia , Psoríase/imunologia , Psoríase/genética , Psoríase/induzido quimicamente , Animais , Camundongos , Interleucina-23/metabolismo , Interleucina-23/genética , Humanos , Inflamação/metabolismo , Inflamação/patologia , Camundongos Knockout , Pele/patologia , Pele/metabolismo , Quinase Induzida por NF-kappaB , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , NF-kappa B/metabolismoRESUMO
The IL-23/IL-17 cytokine axis is related to spondyloarthropathy (SpA) pattern diseases that target the skin, eye, gut and joints. These share overlapping target tissues with Th2 type or allergic diseases, including the skin, eye and gut but SpA diseases exhibit distinct microanatomical topography, molecular characteristics, and clinical features including uveitis, psoriasis, apical pulmonary involvement, lower gastrointestinal involvement with colitis, and related arthritides including psoriatic arthritis and ankylosing spondylitis. Inflammatory arthritis is conspicuously absent from the Th2 diseases which are characterised IL-4/IL-13 dependent pathway activation including allergic rhino-conjunctivitis, atopic eczema, allergic asthma and food allergies. This traditional understanding of non-overlap of musculoskeletal territory between that atopic diseases and the IL-17 -mediated SpA diseases is undergoing a critical reappraisal with the recent demonstration of IL-4/IL-13 blockade, may be associated with the development of SpA pattern arthritis, psoriasiform skin disease and occasional anterior uveitis. Given the known plasticity within Th paradigm pathways, these findings suggest dynamic Th2 cytokine and Th17 cytokine counter regulation in vivo in humans. Unexpected, this is the case in peripheral enthesis and when the IL-4/13 immunological brake on IL-23/17 cytokines is removed, a SpA phenotype may emerge. We discuss hitherto unexpected observations in SpA, showing counter regulation between the Th17 and Th2 pathways at sites including the entheses that collectively indicate that the emergent reverse translational therapeutic data is more than coincidental and offers new insights into the "Th paradigms" in atopy and SpA.