RESUMO
BACKGROUND: Many human diseases arise from or have pathogenic contributions from a dysregulated immune response. One pathway with immunomodulatory ability is the tryptophan metabolism pathway, which promotes immune suppression through the enzyme indoleamine 2,3-dioxygenase (IDO) and subsequent production of kynurenine. However, in patients with chronic inflammatory skin disease, such as psoriasis and atopic dermatitis (AD), another tryptophan metabolism enzyme downstream of IDO, L-kynureninase (KYNU), is heavily upregulated. The role of KYNU has not been explored in patients with these skin diseases or in general human immunology. OBJECTIVE: We sought to explore the expression and potential immunologic function of the tryptophan metabolism enzyme KYNU in inflammatory skin disease and its potential contribution to general human immunology. METHODS: Psoriatic skin biopsy specimens, as well as normal human skin, blood, and primary cells, were used to investigate the immunologic role of KYNU and tryptophan metabolites. RESULTS: Here we show that KYNU(+) cells, predominantly of myeloid origin, infiltrate psoriatic lesional skin. KYNU expression positively correlates with disease severity and inflammation and is reduced on successful treatment of psoriasis or AD. Tryptophan metabolites downstream of KYNU upregulate several cytokines, chemokines, and cell adhesions. By mining data on several human diseases, we found that in patients with cancer, IDO is preferentially upregulated compared with KYNU, whereas in patients with inflammatory diseases, such as AD, KYNU is preferentially upregulated compared with IDO. CONCLUSION: Our results suggest that tryptophan metabolism might dichotomously modulate immune responses, with KYNU as a switch between immunosuppressive versus inflammatory outcomes. Although tryptophan metabolism is increased in many human diseases, how tryptophan metabolism is proceeding might qualitatively affect the immune response in patients with that disease.
Assuntos
Hidrolases/metabolismo , Mediadores da Inflamação/metabolismo , Psoríase/etiologia , Psoríase/metabolismo , Biópsia , Células Cultivadas , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Hidrolases/genética , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/metabolismo , Masculino , Redes e Vias Metabólicas , Células Mieloides/imunologia , Células Mieloides/metabolismo , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Pele/imunologia , Pele/metabolismo , Pele/patologia , Triptofano/metabolismoRESUMO
BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease exhibiting a predominantly T(H)2/"T22" immune activation and a defective epidermal barrier. Narrow-band UVB (NB-UVB) is considered an efficient treatment for moderate-to-severe AD. In patients with psoriasis, NB-UVB has been found to suppress T(H)1/T(H)17 polarization, with subsequent reversal of epidermal hyperplasia. The immunomodulatory effects of this treatment are largely unknown in patients with AD. OBJECTIVE: We sought to evaluate the effects of NB-UVB on immune and barrier abnormalities in patients with AD, aiming to establish reversibility of disease and biomarkers of therapeutic response. METHODS: Twelve patients with moderate-to-severe chronic AD received NB-UVB phototherapy 3 times weekly for up to 12 weeks. Lesional and nonlesional skin biopsy specimens were obtained before and after treatment and evaluated by using gene expression and immunohistochemistry studies. RESULTS: All patients had at least a 50% reduction in SCORAD index scores with NB-UVB phototherapy. The T(H)2, T22, and T(H)1 immune pathways were suppressed, and measures of epidermal hyperplasia and differentiation normalized. The reversal of disease activity was associated with elimination of inflammatory leukocytes and T(H)2/T22- associated cytokines and chemokines and normalized expression of barrier proteins. CONCLUSIONS: Our study shows that resolution of clinical disease in patients with chronic AD is accompanied by reversal of both the epidermal defects and the underlying immune activation. We have defined a set of biomarkers of disease response that associate resolved T(H)2 and T22 inflammation in patients with chronic AD with reversal of barrier pathology. By showing reversal of the AD epidermal phenotype with a broad immune-targeted therapy, our data argue against a fixed genetic phenotype.
Assuntos
Dermatite Atópica/terapia , Terapia Ultravioleta , Adulto , Biomarcadores , Doença Crônica , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Inflamação/terapia , Masculino , Pessoa de Meia-Idade , Pele/imunologia , Pele/patologia , Células Th1/imunologia , Células Th2/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Atopic dermatitis (AD) and psoriasis represent polar immune diseases. AD is a T(H)2/T(H)22-dominant disease, whereas psoriasis is considered a T(H)1/T(H)17 disease. Local immune deviation is suggested to be regulated by dendritic cell (DC)-induced T-cell polarization and recruitment of specific T-cell subsets by chemokines. Although the role of chemokines is well documented, the actual contribution of DCs to activate polar T-cell subsets in human subjects is still a matter of speculation. OBJECTIVE: We sought to elucidate the significance of each cutaneous DC subset in disease-specific T-cell immune deviation. METHODS: We performed a comprehensive analysis of major cutaneous resident (Langerhans cells and blood dendritic cell antigen 1-positive dermal DCs) and inflammatory (inflammatory dendritic epidermal cells and blood dendritic cell antigen 1-negative dermal DCs) DC subsets directly isolated from the lesional skin of patients with AD and those with psoriasis. RESULTS: The ability of each DC subset to expand T(H)1, T(H)2, T(H)17, and T(H)22 subsets was similar between the 2 diseases, despite the association of both with accumulation of resident and inflammatory DCs. We also confirmed differential upregulation of chemokine expression in patients with AD (CCL17, CCL18, and CCL22) and psoriasis (CXCL1, IL-8, and CCL20). The expression of CCL17 and CCL22 was higher in Langerhans cells from patients with AD than from patients with psoriasis, whereas the opposite was observed for CXCL9 and CXCL10. CONCLUSION: Our results suggest that DC polarity does not directly drive differential T-cell subset responses. Alternatively, disease-specific chemokines might recruit specific memory T-cell subsets into the skin, which in turn might be activated and expanded by DCs at the site of inflammation, maintaining differential immune polarity in these diseases.
Assuntos
Células Dendríticas/imunologia , Dermatite Atópica/imunologia , Psoríase/imunologia , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Quimiocinas/imunologia , Quimiocinas/metabolismo , Humanos , Ativação Linfocitária/imunologia , Pele/patologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologiaRESUMO
BACKGROUND: Previous work has identified CD11c(+)CD1c(-) dendritic cells (DCs) as the major "inflammatory" dermal DC population in patients with psoriasis vulgaris and CD1c(+) DCs as the "resident" cutaneous DC population. OBJECTIVE: We sought to further define molecular differences between these 2 myeloid dermal DC populations. METHODS: Inflammatory and resident DCs were single-cell sorted from lesional skin biopsy specimens of patients with psoriasis, and the transcriptome of CD11c(+)CD1c(-) versus CD1c(+) DCs was determined. Results were confirmed with RT-PCR, flow cytometry, immunohistochemistry, and double-labeled immunofluorescence. Human keratinocytes were cultured for functional studies. RESULTS: TNF-related apoptosis-inducing ligand (TRAIL), Toll-like receptors 1 and 2, S100A12/ENRAGE, CD32, and many other inflammatory products were differentially expressed in inflammatory DCs compared with resident DCs. Flow cytometry and immunofluorescence confirmed higher protein expression on CD1c(-) versus CD1c(+) DCs. TRAIL receptors, death receptor 4, and decoy receptor 2 were expressed in keratinocytes and dermal cells. In vitro culture of keratinocytes with TRAIL induced CCL20 chemokine. CONCLUSIONS: CD11c(+)CD1c(-) inflammatory DCs in psoriatic lesional skin express a wide range of inflammatory molecules compared with skin-resident CD1c(+) DCs. Some molecules made by inflammatory DCs, including TRAIL, could have direct effects on keratinocytes or other skin cell types to promote disease pathogenesis.
Assuntos
Biomarcadores/metabolismo , Células de Langerhans/metabolismo , Psoríase/diagnóstico , Psoríase/imunologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Diferenciação Celular , Separação Celular , Células Cultivadas , Quimiocina CCL20/biossíntese , Quimiocina CCL20/genética , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Inflamação , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Células de Langerhans/imunologia , Células de Langerhans/patologia , Análise em Microsséries , Psoríase/patologia , Proteínas S100/biossíntese , Proteínas S100/genética , Receptores Chamariz do Fator de Necrose Tumoral/biossíntese , Receptores Chamariz do Fator de Necrose Tumoral/genéticaRESUMO
INTRODUCTION: Inflammatory skin diseases can be examined from many viewpoints. In this review, we consider three distinct cutaneous inflammatory diseases from the point of view of their major lesional dendritic cell (DC) subpopulations. The DC populations considered are Langerhans cells, myeloid DCs, and plasmacytoid DCs (pDCs), with specific attention to the presence and role of the inflammatory counterparts of these cells. From such a "dendritic cell-centric" focus, psoriasis, atopic dermatitis (AD), and cutaneous lupus erythematosus (CLE) are explored. DISCUSSION: In psoriasis, there is a specific population of myeloid "inflammatory" DCs that appears to play an important pathogenic role, while pDCs have been recently implicated in the initiation of psoriatic lesions. In AD, Langerhans cells may be important during initiation, while "inflammatory dendritic epidermal cells" (IDECs) appear to be abundant in lesional epidermis and dermis and contribute to maintenance of AD. These IDECs may actually be analogous to the myeloid inflammatory DCs found in the epidermal and dermal compartments of the skin in psoriasis, although they express distinct surface markers and induce different T cell polarities as a result of different cytokine milieu in which they develop. CLE has been recently characterized as a type I IFN-mediated disease, and pDCs are integral to the pathogenesis of this disease. CONCLUSION: Thus, these DC subpopulations and their products will be reviewed in the context of these three cutaneous diseases to provide clinico-pathophysiological correlations between the lesional DCs, their products, and the skin diseases.
Assuntos
Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Dermatite Atópica/imunologia , Lúpus Eritematoso Cutâneo/imunologia , Psoríase/imunologia , Animais , Apresentação de Antígeno , Movimento Celular , Citocinas/biossíntese , Células Dendríticas/patologia , Dermatite Atópica/patologia , Dermatite Atópica/fisiopatologia , Humanos , Inflamação , Lúpus Eritematoso Cutâneo/patologia , Lúpus Eritematoso Cutâneo/fisiopatologia , Psoríase/patologia , Psoríase/fisiopatologiaRESUMO
BACKGROUND: IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. METHODOLOGY/PRINCIPAL FINDINGS: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -ß, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes. CONCLUSIONS/SIGNIFICANCE: The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the "RHE" genes in psoriasis patients treated in vivo with this IL-17 antagonist.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Epiderme/efeitos dos fármacos , Interleucina-17/farmacologia , Queratinócitos/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Células Epidérmicas , Epiderme/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Lipocalinas/genética , Lipocalinas/metabolismo , Técnicas de Cultura de Tecidos , Engenharia Tecidual , beta-Defensinas/genética , beta-Defensinas/metabolismoRESUMO
The acute response of human skin to UVB radiation has not been fully characterized. We sought to define the cutaneous response at 24 hours following narrowband UVB (NB-UVB, 312-nm peak), a therapeutically relevant source of UVB, using transcriptional profiling, immunohistochemistry, and immunofluorescence. There were 1,522 unique differentially regulated genes, including upregulated genes encoding antimicrobial peptides (AMPs) (S100A7, S100A12, human beta-defensin 2, and elafin), as well as neutrophil and monocyte/dendritic cell (DC) chemoattractants (IL-8, CXCL1, CCL20, CCL2). Ingenuity pathway analysis demonstrated activation of innate defense and early adaptive immune pathways. Immunohistochemistry confirmed increased epidermal staining for AMPs (S100A7, S100A12, human beta-defensin 2, and elafin). Inflammatory myeloid CD11c(+)BDCA1(-) DCs were increased in irradiated skin, which were immature as shown by minimal colocalization with DC-LAMP, and coexpressed inflammatory markers tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand in irradiated skin. There were increased BDCA3(+) DCs, a cross-presenting DC subtype with immunosuppressive functions, and these cells have not been previously characterized as part of the response to UVB. These results show that the acute response of human skin to erythemogenic doses of NB-UVB includes activation of innate defense mechanisms, as well as early infiltration of multiple subtypes of inflammatory DCs, which could serve as a link between innate and adaptive immunity.
Assuntos
Perfilação da Expressão Gênica , Imunidade Celular/genética , Imunidade Inata/genética , Pele/lesões , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Imunidade Adaptativa/efeitos da radiação , Adulto , Idoso , Biópsia , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Elafina/genética , Elafina/metabolismo , Feminino , Humanos , Imunidade Celular/efeitos da radiação , Imunidade Inata/efeitos da radiação , Células de Langerhans/patologia , Células de Langerhans/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Proteína A7 Ligante de Cálcio S100 , Proteínas S100/genética , Proteínas S100/metabolismo , Proteína S100A12 , Transdução de Sinais/efeitos da radiação , Pele/imunologia , beta-Defensinas/genética , beta-Defensinas/metabolismoRESUMO
Our group recently described a population of antigen-presenting cells that appear to be critical in psoriasis pathogenesis, termed inflammatory myeloid dendritic cells (CD11c(+)/blood dendritic cell (DC) antigen 1(-)). Triggering receptor expressed on myeloid cells type-1 (TREM-1) signaling was a major canonical pathway in the published transcriptome of these cells. TREM-1 is a member of the Ig superfamily, active through the DAP12 signaling pathway, with an unknown ligand. Activation through TREM-1 induces inflammatory cytokines, including IL-8, MCP/CCL2, and tumor necrosis factor. We now show that TREM-1 was expressed in the skin of healthy and psoriatic patients, and there was increased soluble TREM-1 in the circulation of psoriasis patients. In psoriasis lesions, TREM-1 was colocalized with DCs, as well as CD31(+) endothelial cells. TREM-1 expression was reduced with successful narrow band UVB (NB-UVB), etanercept, and anti-IL-17 treatments. An in vitro model of peptidoglycan-activated monocytes as inflammatory myeloid DCs was developed to study TREM-1 blockade, and treatment with a TREM-1 blocking chimera decreased allogeneic T-helper type 17 cell activation, as well as IL-17 production. Furthermore, TREM-1 blockade of ex vivo psoriatic DCs in an allogeneic mixed leukocyte reaction also showed a decrease in IL-17. Together, these data suggest that the TREM-1 signaling pathway may be a previously unidentified therapeutic target to prevent the effects of inflammatory myeloid DCs in psoriasis.
Assuntos
Células de Langerhans/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Psoríase/metabolismo , Psoríase/terapia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Transdução de Sinais/fisiologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antígeno CD11c/metabolismo , Células Cultivadas , Citocinas/metabolismo , Etanercepte , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Técnicas In Vitro , Interleucina-17/metabolismo , Células de Langerhans/imunologia , Células de Langerhans/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Psoríase/patologia , Receptores do Fator de Necrose Tumoral/uso terapêutico , Células Th17/metabolismo , Células Th17/patologia , Receptor Gatilho 1 Expresso em Células Mieloides , Terapia UltravioletaRESUMO
Psoriasis vulgaris is a chronic, debilitating skin disease that affects millions of people worldwide. There is no mouse model that accurately reproduces all facets of the disease, but the accessibility of skin tissue from patients has facilitated the elucidation of many pathways involved in the pathogenesis of psoriasis and highlighted the importance of the immune system in the disease. The pathophysiological relevance of these findings has been supported by genetic studies that identified polymorphisms in genes associated with NFκB activation, IL-23 signaling and T helper 17 (Th17)-cell adaptive immune responses, and in genes associated with the epidermal barrier. Recently developed biologic agents that selectively target specific components of the immune system are highly effective for treating psoriasis. In particular, emerging therapeutics are focused on targeting the IL-23-Th17-cell axis, and several agents that block IL-17 signaling have shown promising results in early-phase clinical trials. This review discusses lessons learned about the pathogenesis of psoriasis from mouse-and patient-based studies, emphasizing how the outcomes of clinical trials with T-cell-targeted and cytokine-blocking therapies have clarified our understanding of the disease.
Assuntos
Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Psoríase/terapia , Animais , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Modelos Imunológicos , Psoríase/etiologia , Psoríase/genética , Psoríase/imunologia , Linfócitos T/imunologiaRESUMO
In the early stages of wound healing, keratinocytes (KCs) become "activated" and release inflammatory molecules such as IL-1 and IL-8, which are linked to innate immune responses and neutrophil recruitment. It is unclear, however, whether KCs release molecules linked to adaptive immune responses, e.g., CCL20, in their early state of activation without signals from infiltrating T cells. This study aims to isolate the immediate alterations in protective and inflammatory gene expression that occur in epidermal KCs, with a particular focus on molecules associated with cell-mediated immunity. We used dispase-separated epidermis, followed by intercellular disassociation by trypsinization, as a model for epidermal injury. We obtained a pure population of KCs using flow cytometry. As a control for uninjured epidermis, we performed laser capture microdissection on normal human skin. Sorted KCs had an early burst of upregulated gene expression, which included CCL20, IL-15, IL-23A, IFN-κ, and several antimicrobial peptides. Our results provide insight into the potential role of KCs as contributors to cell-mediated inflammation, and expand knowledge about gene modulation that occurs during early wound healing. Our findings may be relevant to cutaneous diseases such as psoriasis, where micro-injury can trigger the formation of psoriatic plaques at the site of trauma.
Assuntos
Quimiocina CCL20/imunologia , Epiderme/imunologia , Epiderme/lesões , Imunidade Inata/imunologia , Queratinócitos/imunologia , Psoríase/imunologia , Imunidade Adaptativa , Adulto , Células Cultivadas , Quimiocina CCL20/genética , Dermatite/imunologia , Dermatite/patologia , Células Epidérmicas , Citometria de Fluxo , Expressão Gênica/imunologia , Humanos , Queratinócitos/citologia , Microdissecção e Captura a Laser , Psoríase/patologia , Regulação para Cima/imunologia , Cicatrização/imunologiaRESUMO
UNLABELLED: To understand the development of new psoriasis lesions, we studied a group of moderate-to-severe psoriasis patients who experienced a relapse after ceasing efalizumab (anti-CD11a, Raptiva, Genentech). There were increased CD3(+) T cells, neutrophils, CD11c(+) and CD83(+) myeloid dendritic cells (DCs), but no increase in CD1c(+) resident myeloid DCs. In relapsed lesions, there were many CD11c(+)CD1c(-), inflammatory myeloid DCs identified by TNFSF10/TRAIL, TNF, and iNOS. CD11c(+) cells in relapsed lesions co-expressed CD14 and CD16 in situ. Efalizumab induced an improvement in many psoriasis genes, and during relapse, the majority of these genes reversed back to a lesional state. Gene Set Enrichment Analysis (GSEA) of the transcriptome of relapsed tissue showed that many of the gene sets known to be present in psoriasis were also highly enriched in relapse. Hence, on ceasing efalizumab, T cells and myeloid cells rapidly enter the skin to cause classic psoriasis. TRIAL REGISTRATION: Clinicaltrials.gov NCT00115076.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno CD11a/efeitos dos fármacos , Células Dendríticas , Psoríase , Linfócitos T , Anticorpos Monoclonais Humanizados , Inibição de Migração Celular , Movimento Celular , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Humanos , Imunofenotipagem , Inflamação/patologia , Masculino , Células Mieloides , Psoríase/tratamento farmacológico , Psoríase/genética , Psoríase/patologia , Recidiva , Linfócitos T/imunologia , Linfócitos T/patologia , TranscriptomaRESUMO
Psoriasis is a chronic, debilitating, immune-mediated inflammatory skin disease. As IFN-γ is involved in many cellular processes, including activation of dendritic cells (DCs), antigen processing and presentation, cell adhesion and trafficking, and cytokine and chemokine production, IFN-γ-producing Th1 cells were proposed to be integral to the pathogenesis of psoriasis. Recently, IFN-γ was shown to enhance IL-23 and IL-1 production by DCs and subsequently induce Th17 cells, which are important contributors to the inflammatory cascade in psoriatic lesions. To determine whether IFN-γ indeed induces the pathways expressed in psoriatic lesions, a single intradermal injection of IFN-γ was administered to an area of clinically normal, non-lesional (NL) skin of psoriasis patients and biopsies were collected 24 hours later. Although there were no visible changes in the skin, IFN-γ induced many molecular and histological features characteristic of psoriatic lesions. IFN-γ increased a number of differentially expressed genes in the skin, including many chemokines concomitant with an influx of T cells and inflammatory DCs. Furthermore, inflammatory DC products tumor necrosis factor (TNF), inducible nitric oxide synthase, IL-23, and TNF-related apoptosis-inducing ligand were present in IFN-γ-treated skin. Thus, IFN-γ, which is significantly elevated in NL skin compared with healthy skin, appears to be a key pathogenic cytokine that can induce many features of the inflammatory cascade of psoriasis.
Assuntos
Inflamação/metabolismo , Inflamação/patologia , Interferon gama/farmacologia , Psoríase/metabolismo , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/metabolismo , Biópsia , Estudos de Casos e Controles , Movimento Celular , Células Dendríticas/patologia , Humanos , Inflamação/induzido quimicamente , Injeções Intradérmicas , Interferon gama/administração & dosagem , Interferon gama/efeitos adversos , Interleucina-23/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , Pele/patologia , Linfócitos T/patologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in CIAS1 that result in increased production and secretion of active IL-1ß. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bone, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (nâ=â14) before treatment (lesional (LS) and non-lesional (pre-NL) skin) and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®, Swedish Orphan Biovitrum AB, SOBI), to normal skin (nâ=â5) to assess tissue responses in the context of untreated and treated disease. Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c(+) dermal dendritic cells and CD163(+) macrophages expressed activated caspase-1 and are a likely source of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3(+) T cells and HLA-DR(+) cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways in LS skin included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. The differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification were suggestive of epigenetic modification in the chronically inflamed tissue. Overall, the dysregulated genes and pathways suggest extensive "adaptive" mechanisms to control inflammation and maintain tissue homeostasis, likely triggered by chronic IL-1 release in the skin of patients with NOMID.
Assuntos
Síndromes Periódicas Associadas à Criopirina/imunologia , Homeostase/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/genética , Receptores de Interleucina-1/genética , Pele/imunologia , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Biópsia , Caspase 1/genética , Caspase 1/imunologia , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/patologia , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/imunologia , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Homeostase/genética , Homeostase/imunologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/imunologia , Células de Langerhans/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , MicroRNAs/genética , MicroRNAs/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/imunologia , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Tumor-associated macrophages (TAMs) may have an important role in tumor immunity. We studied the activation state of TAMs in cutaneous SCC, the second most common human cancer. CD163 was identified as a more abundant, sensitive, and accurate marker of TAMs when compared with CD68. CD163(+) TAMs produced protumoral factors, matrix metalloproteinases 9 and 11 (MMP9 and MMP11), at the gene and protein levels. Gene set enrichment analysis (GSEA) was used to evaluate M1 and M2 macrophage gene sets in the SCC genes and to identify candidate genes in order to phenotypically characterize TAMs. There was coexpression of CD163 and alternatively activated "M2" markers, CD209 and CCL18 (chemokine (C-C motif) ligand 18). There was enrichment for classically activated "M1" genes in SCC, which was confirmed in situ by colocalization of CD163 and phosphorylated STAT1 (signal transducer and activator of transcription 1), IL-23p19, IL-12/IL-23p40, and CD127. Also, a subset of TAMs in SCC was bi-activated as CD163(+) cells expressed markers for both M1 and M2, shown by triple-label immunofluorescence. These data support heterogeneous activation states of TAMs in SCC, and suggest that a dynamic model of macrophage activation would be more useful to characterize TAMs.
Assuntos
Carcinoma de Células Escamosas/imunologia , Ativação de Macrófagos , Neoplasias Cutâneas/imunologia , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Humanos , Receptores de Superfície Celular/análise , Receptores de Interferon/fisiologia , Pele/imunologia , Receptor de Interferon gamaRESUMO
Narrow-band UVB radiation (NB-UVB) therapy offers a well-established treatment modality for psoriasis. However, despite the common use of this form of treatment, the mechanism of action of NB-UVB is not well understood. We studied a group of 14 patients with moderate-to-severe psoriasis treated with carefully titrated and monitored NB-UVB for 6 weeks. Lesional plaques were classified as normalized (n=8) or nonresponsive (n=6) based on their histological improvement and normalization. We characterized lesional myeloid dendritic cells (DCs) and T cells and their inflammatory mediators using immunohistochemistry and real-time PCR. NB-UVB suppressed multiple parameters of the IL-23/IL-17 pathway in normalized plaques, but not in nonresponsive plaques. NB-UVB decreased the numbers of CD11c(+) DCs, specifically CD1c(-)CD11c(+) "inflammatory" DCs, and their products, IL-20, inducible nitric oxide synthase, IL-12/23p40, and IL-23p19. Furthermore, effective NB-UVB suppressed IL-17 and IL-22 mRNAs, which strongly correlated with lesion resolution. Therefore, in addition to its known role in suppressing IFN-γ production, NB-UVB radiation therapy can also target the IL-17 pathway to resolve psoriatic inflammation.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.