RESUMO
The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The association between comorbidities and psoriasis is reviewed by correlating the skin transcriptome and serum proteins. Psoriasis-related cytokine-response pathways are considered in the context of the transcriptome of different mouse models. This approach offers a model for other inflammatory skin and autoimmune diseases.
Assuntos
Psoríase/imunologia , Animais , Comorbidade , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Camundongos , Psoríase/diagnóstico , Psoríase/genética , Pele/imunologia , Pele/patologia , Fenômenos Fisiológicos da Pele/imunologiaRESUMO
Aberrant RNA splicing in keratinocytes drives inflammatory skin disorders. In the present study, we found that the RNA helicase DDX5 was downregulated in keratinocytes from the inflammatory skin lesions in patients with atopic dermatitis and psoriasis, and that mice with keratinocyte-specific deletion of Ddx5 (Ddx5∆KC) were more susceptible to cutaneous inflammation. Inhibition of DDX5 expression in keratinocytes was induced by the cytokine interleukin (IL)-17D through activation of the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway and led to pre-messenger RNA splicing events that favored the production of membrane-bound, intact IL-36 receptor (IL-36R) at the expense of soluble IL-36R (sIL-36R) and to the selective amplification of IL-36R-mediated inflammatory responses and cutaneous inflammation. Restoration of sIL-36R in Ddx5∆KC mice with experimental atopic dermatitis or psoriasis suppressed skin inflammation and alleviated the disease phenotypes. These findings indicate that IL-17D modulation of DDX5 expression controls inflammation in keratinocytes during inflammatory skin diseases.
Assuntos
Dermatite Atópica , Interleucina-27 , Psoríase , Camundongos , Animais , Interleucina-27/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/patologia , Queratinócitos/metabolismo , Pele/patologia , Psoríase/genética , Psoríase/patologia , Inflamação/metabolismoRESUMO
Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C to mediate its stability, glycosylation and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17R signaling complex. Accordingly, CMTM4-deficient mice had a severe defect in the recruitment of immune cells following IL-17A administration and were largely resistant to experimental psoriasis, but not to experimental autoimmune encephalomyelitis. Collectively, our data identified CMTM4 as an essential component of IL-17R and a potential therapeutic target for treating IL-17-mediated autoimmune diseases.
Assuntos
Artrite Psoriásica , Encefalomielite Autoimune Experimental , Psoríase , Humanos , Camundongos , Animais , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Interleucina-17/metabolismo , Encefalomielite Autoimune Experimental/genética , Proteínas com Domínio MARVEL/genéticaRESUMO
Skin inflammation is potentiated by coordinated epithelial and immune cell metabolism. In this issue of Immunity, Subudhi and Konieczny et al. delineate how HIF1α regulates epithelial cell glycolysis during psoriasis. In turn, lactate is a byproduct that augments type 17 γδ T cell responses to sustain inflammatory skin disease.
Assuntos
Células Epiteliais , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia , Psoríase , Pele , Animais , Humanos , Doença Crônica , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Psoríase/imunologia , Psoríase/metabolismo , Pele/imunologia , Pele/patologia , Pele/metabolismoRESUMO
Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.
Assuntos
Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia , Interleucina-17 , Animais , Humanos , Interleucina-17/metabolismo , Interleucina-17/imunologia , Camundongos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pele/imunologia , Pele/patologia , Pele/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 1/genética , Psoríase/imunologia , Psoríase/metabolismo , Epitélio/imunologia , Epitélio/metabolismo , Camundongos Knockout , Transdução de Sinais/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Modelos Animais de Doenças , Ácido Láctico/metabolismo , Doença Crônica , Inflamação/imunologia , Camundongos Endogâmicos C57BLRESUMO
Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-ß-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.
Assuntos
Autoimunidade , Citocinas , Lúpus Eritematoso Sistêmico , Transdução de Sinais , Espermina , Animais , Espermina/metabolismo , Espermina/farmacologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Camundongos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Citocinas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Janus Quinase 1/metabolismo , Fosforilação , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Psoríase/imunologia , Psoríase/metabolismo , Camundongos Endogâmicos C57BL , Janus Quinases/metabolismo , Feminino , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/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
Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1α, IL-1ß, IL-33, IL-36α, IL-36ß and IL-36γ). In many diseases, multiple cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.
Assuntos
Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/farmacologia , Proteína Acessória do Receptor de Interleucina-1/antagonistas & inibidores , Peritonite/imunologia , Pneumonia/imunologia , Psoríase/imunologia , Células A549 , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HEK293 , Humanos , Imiquimode/toxicidade , Inflamação/patologia , Interleucina-1/imunologia , Proteína Acessória do Receptor de Interleucina-1/imunologia , Interleucina-1beta/imunologia , Interleucina-33/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/toxicidade , Peritonite/tratamento farmacológico , Peritonite/patologia , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Psoríase/tratamento farmacológico , Psoríase/patologia , Transdução de Sinais/imunologia , Ácido Úrico/toxicidadeRESUMO
Here we identify a group 2 innate lymphoid cell (ILC2) subpopulation that can convert into interleukin-17 (IL-17)-producing NKp44- ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation that exhibits ILC3 features, including RORγt, enabling the conversion into IL-17-producing cells in response to IL-1ß and IL-23. We also report a role for transforming growth factor-ß in promoting the conversion of c-Kit- ILC2s into RORγt-expressing cells by inducing the upregulation of IL23R, CCR6 and KIT messenger RNA in these cells. This switch was dependent on RORγt and the downregulation of GATA-3. IL-4 was able to reverse this event, supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance because a subset of RORγt+ ILC2s express the skin-homing receptor CCR10, and the frequencies of IL-17-producing ILC3s are increased at the expense of ILC2s within the lesional skin of patients with psoriasis.
Assuntos
Interleucina-17/imunologia , Linfócitos/imunologia , Psoríase/patologia , Pele/patologia , Células Cultivadas , Humanos , Interleucina-1beta/imunologia , Subunidade p19 da Interleucina-23/imunologia , Interleucina-4/imunologia , Linfócitos/citologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Psoríase/imunologia , Receptores CCR10/metabolismo , Pele/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
IL-17A both directly induces and synergizes with other cytokines to promote autoimmune tissue inflammation. Secukinumab and ixekizumab are monoclonal antibodies (mAb) that inhibit interleukin-17A. These two agents were recently approved for treatment of psoriasis, and secukinumab is also approved for treatment of two spondyloarthropathies, psoriatic arthritis and ankylosing spondylitis.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , HumanosRESUMO
The skin provides both a physical barrier and an immunologic barrier to external threats. The protective machinery of the skin has evolved to provide situation-specific responses to eliminate pathogens and to provide protection against physical dangers. Dysregulation of this machinery can give rise to the initiation and propagation of inflammatory loops in the epithelial microenvironment that result in inflammatory skin diseases in susceptible people. A defective barrier and microbial dysbiosis drive an interleukin 4 (IL-4) loop that underlies atopic dermatitis, while in psoriasis, disordered keratinocyte signaling and predisposition to type 17 responses drive a pathogenic IL-17 loop. Here we discuss the pathogenesis of atopic dermatitis and psoriasis in terms of the epithelial immune microenvironment-the microbiota, keratinocytes and sensory nerves-and the resulting inflammatory loops.
Assuntos
Dermatite Atópica/imunologia , Psoríase/imunologia , Pele/imunologia , Animais , Dermatite Atópica/microbiologia , Dermatite Atópica/fisiopatologia , Disbiose/imunologia , Disbiose/microbiologia , Disbiose/fisiopatologia , Epitélio/imunologia , Epitélio/microbiologia , Epitélio/fisiopatologia , Humanos , Psoríase/microbiologia , Psoríase/fisiopatologia , Pele/microbiologiaRESUMO
Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1-P3). P1-pDCs (PD-L1+CD80-) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1-CD80+) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1+CD80+) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.
Assuntos
Citocinas/imunologia , Células Dendríticas/imunologia , Expressão Gênica/imunologia , Imunidade Inata/imunologia , Imunidade Adaptativa/imunologia , Antígeno B7-1/imunologia , Antígeno B7-1/metabolismo , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/ultraestrutura , Perfilação da Expressão Gênica/métodos , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Microscopia Eletrônica de Transmissão , Orthomyxoviridae/imunologia , Psoríase/imunologiaRESUMO
Increased understanding of the biology of interleukin 17 (IL-17) has revealed that this cytokine is a central player in immunity at the sites most exposed to microorganisms. Although it has been strongly associated with immunopathology, IL-17 also has an important role in host defense. The regulation of IL-17 secretion seems to be shared among various cell types, each of which can concomitantly secrete additional products. IL-17 has only modest activity on its own; its impact in immunity arises from its synergistic action with other factors, its self-sustaining feedback loop and, in some cases, its role as a counterpart of interferon-γ (IFN-γ). Together these attributes provide a robust response against microorganisms, but they can equally contribute to immune pathology. Here we focus on a discussion of the role of IL-17 during infection.
Assuntos
Imunidade Adaptativa/imunologia , Artrite Reumatoide/imunologia , Imunidade Inata/imunologia , Infecções/imunologia , Interleucina-17/imunologia , Neoplasias/imunologia , Psoríase/imunologia , Animais , Retroalimentação , Humanos , Interferon gama/imunologia , CamundongosRESUMO
The role of keratinocyte metabolism in psoriasis is not fully elucidated. In this issue of Immunity, Lou et al. describe that interleukin-17 (IL-17) re-programs the urea cycle in keratinocytes increasing polyamines that stabilize RNA-Ag-complexes that upon cellular turnover activate dendritic cells, which amplify psoriasis inflammation.
Assuntos
Psoríase , RNA , Células Dendríticas , Humanos , Queratinócitos , PoliaminasRESUMO
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
The activation marker CD69 is expressed by skin γδ T cells. Here we found that CD69 controlled the aryl hydrocarbon receptor (AhR)-dependent secretion of interleukin 22 (IL-22) by γδ T cells, which contributed to the development of psoriasis induced by IL-23. CD69 associated with the aromatic-amino-acid-transporter complex LAT1-CD98 and regulated its surface expression and uptake of L-tryptophan (L-Trp) and the intracellular quantity of L-Trp-derived activators of AhR. In vivo administration of L-Trp, an inhibitor of AhR or IL-22 abrogated the differences between CD69-deficient mice and wild-type mice in skin inflammation. We also observed LAT1-mediated regulation of AhR activation and IL-22 secretion in circulating Vγ9(+) γδ T cells of psoriatic patients. Thus, CD69 serves as a key mediator of the pathogenesis of psoriasis by controlling LAT1-CD98-mediated metabolic cues.
Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Lectinas Tipo C/metabolismo , Psoríase/imunologia , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+L de Transporte de Aminoácidos , Animais , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Células Cultivadas , Endocitose , Proteína-1 Reguladora de Fusão/metabolismo , Interleucina-23/imunologia , Interleucinas/metabolismo , Lectinas Tipo C/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo , Interleucina 22RESUMO
CD1a is a lipid-presenting molecule that is abundantly expressed on Langerhans cells. However, the in vivo role of CD1a has remained unclear, principally because CD1a is lacking in mice. Through the use of mice with transgenic expression of CD1a, we found that the plant-derived lipid urushiol triggered CD1a-dependent skin inflammation driven by CD4(+) helper T cells that produced the cytokines IL-17 and IL-22 (TH17 cells). Human subjects with poison-ivy dermatitis had a similar cytokine signature following CD1a-mediated recognition of urushiol. Among various urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells. We determined the crystal structure of the CD1a-urushiol (C15:2) complex, demonstrating the molecular basis of urushiol interaction with the antigen-binding cleft of CD1a. In a mouse model and in patients with psoriasis, CD1a amplified inflammatory responses that were mediated by TH17 cells that reacted to self lipid antigens. Treatment with blocking antibodies to CD1a alleviated skin inflammation. Thus, we propose CD1a as a potential therapeutic target in inflammatory skin diseases.
Assuntos
Antígenos CD1/metabolismo , Autoantígenos/metabolismo , Catecóis/metabolismo , Dermatite por Toxicodendron/imunologia , Células de Langerhans/imunologia , Psoríase/imunologia , Células Th17/imunologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Antígenos CD1/genética , Antígenos CD1/imunologia , Catecóis/química , Cristalografia por Raios X , Modelos Animais de Doenças , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Conformação Proteica , Toxicodendron/imunologia , Interleucina 22RESUMO
BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).