RESUMO
RATIONALE: Psoriasis is a chronic inflammatory skin disease involving different cytokines and chemokines. OBJECTIVES: Here we use single-cell transcriptomic analyses to identify relevant immune cell and nonimmune cell populations for an in-depth characterization of cell types and inflammatory mediators in this disease. METHODS: Psoriasis skin lesions of eight patients are analyzed using single-cell technology. Data are further validated by in situ hybridization (ISH) of human tissues, serum analyses of human samples and tissues of a murine model of psoriasis, and by in vitro cell culture experiments. RESULTS: Several different immune-activated cell types with particular cytokine patterns are identified such as keratinocytes, T-helper cells, dendritic cells, macrophages, and fibroblasts. Apart from well-known factors, IL-14 (TXLNA), IL-18, and IL-32 are identified with prominent expression in individual cell types in psoriasis. The percentage of inflammatory cellular subtypes expressing IL-14, IL-18, and IL-32 was significantly higher in psoriatic skin compared with healthy control skin. These findings were confirmed by ISH of human skin samples, in a murine model of psoriasis, in human serum samples, and in in vitro experiments. CONCLUSIONS: Taken together, we provide a differentiated view of psoriasis immune-cell phenotypes that support the role of IL-14, IL-18, and IL-32 in psoriasis pathogenesis.
Assuntos
Interleucina-18 , Psoríase , Humanos , Camundongos , Animais , Interleucina-18/genética , Interleucina-18/metabolismo , Modelos Animais de Doenças , Transcriptoma , Psoríase/genética , Pele/patologia , Queratinócitos , Citocinas/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
BACKGROUND AND AIMS: Steatotic liver disease (SLD) is generally considered to represent a hepatic manifestation of metabolic syndrome and includes a disease spectrum comprising isolated steatosis, metabolic dysfunction-associated steatohepatitis, liver fibrosis and ultimately cirrhosis. A better understanding of the detailed underlying pathogenic mechanisms of this transition is crucial for the design of new and efficient therapeutic interventions. Thymocyte differentiation antigen (Thy-1, also known as CD90) expression on fibroblasts controls central functions relevant to fibrogenesis, including proliferation, apoptosis, cytokine responsiveness, and myofibroblast differentiation. METHODS: The impact of Thy-1 on the development of SLD and progression to fibrosis was investigated in high-fat diet (HFD)-induced SLD wild-type and Thy-1-deficient mice. In addition, the serum soluble Thy-1 (sThy-1) concentration was analysed in patients with metabolic dysfunction-associated SLD stratified according to steatosis, inflammation, or liver fibrosis using noninvasive markers. RESULTS: We demonstrated that Thy-1 attenuates the development of fatty liver and the expression of profibrogenic genes in the livers of HFD-induced SLD mice. Mechanistically, Thy-1 directly inhibits the profibrotic activation of nonparenchymal liver cells. In addition, Thy-1 prevents palmitic acid-mediated amplification of the inflammatory response of myeloid cells, which might indirectly contribute to the pronounced development of liver fibrosis in Thy-1-deficient mice. Serum analysis of patients with metabolically associated steatotic liver disease syndrome revealed that sThy-1 expression is correlated with liver fibrosis status, as assessed by liver stiffness, the Fib4 score, and the NAFLD fibrosis score. CONCLUSION: Our data strongly suggest that Thy-1 may function as a fibrosis-protective factor in mouse and human SLD.
Assuntos
Dieta Hiperlipídica , Cirrose Hepática , Camundongos Endogâmicos C57BL , Antígenos Thy-1 , Animais , Cirrose Hepática/patologia , Camundongos , Humanos , Antígenos Thy-1/metabolismo , Masculino , Camundongos Knockout , Modelos Animais de Doenças , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado/patologia , Fígado/metabolismo , Fígado Gorduroso/patologia , Pessoa de Meia-Idade , FemininoRESUMO
Kidney fibrosis is a major culprit in the development and progression of chronic kidney disease (CKD), ultimately leading to the irreversible loss of organ function. Thymocyte differentiation antigen-1 (Thy-1) controls many core functions of fibroblasts relevant to fibrogenesis but is also found in a soluble form (sThy-1) in serum and urine. We investigated the association of sThy-1 with clinical parameters in patients with CKD receiving hemodialysis treatment compared to individuals with a preserved renal function. Furthermore, Thy-1 tissue expression was detected in a mouse model of diabetic CKD (eNOS-/-; db/db) and non-diabetic control mice (eNOS-/-). Serum and urinary sThy-1 concentrations significantly increased with deteriorating renal function, independent of the presence of diabetes. Serum creatinine is the major, independent, and inverse predictor of serum sThy-1 levels. Moreover, sThy-1 is not only predicted by markers of renal function but is also itself an independent and strong predictor of markers of renal function, i.e., serum creatinine. Mice with severe diabetic CKD show increased Thy-1 mRNA and protein expression in the kidney compared to control animals, as well as elevated urinary sThy-1 levels. Pro-fibrotic mediators, such as interleukin (IL)-4, IL-13, IL-6 and transforming growth factor ß, increase Thy-1 gene expression and release of sThy-1 from fibroblasts. Our data underline the role of Thy-1 in the control of kidney fibrosis in CKD and raise the opportunity that Thy-1 may function as a renal antifibrotic factor.
Assuntos
Insuficiência Renal Crônica , Camundongos , Animais , Creatinina/metabolismo , Insuficiência Renal Crônica/metabolismo , Rim/metabolismo , Fibrose , Fibroblastos/metabolismo , Antígenos Thy-1/metabolismoRESUMO
Balanced differentiation of mesenchymal stromal cells (MSCs) into osteoblasts and adipocytes is essential for healthy bone and fat homeostasis. A disturbed balance of MSC differentiation results in bone loss and increased adipogenesis as observed in several human conditions, such as osteoporosis, obesity, and aging. This reflects the importance of MSC fate decision. Therefore, it is important to identify factors that regulate the balance between osteogenic and adipogenic differentiation of MSCs so as to identify new targets to improve bone formation in osteoporosis and control adipose tissue development. There is accumulating evidence that thymus cell antigen 1 (Thy-1), also known as CD90, expressed on MSCs, plays a critical role in the fate decision of MSCs. Recently, Thy-1 has been shown to promote osteogenic differentiation of MSCs and thus bone formation while inhibiting adipogenic differentiation and restricting adipose tissue accumulation. The clinical importance of these findings was validated by the detection of reduced serum soluble Thy-1 in patients with disturbed bone remodeling. In this review, we aim to summarize data on the impact of Thy-1 on the control of MSC differentiation and its consequences for bone and fat formation.-Saalbach, A., Anderegg, U. Thy-1: more than a marker for mesenchymal stromal cells.
Assuntos
Adipócitos/citologia , Biomarcadores/metabolismo , Diferenciação Celular , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Antígenos Thy-1/metabolismo , Adipócitos/metabolismo , Adipogenia , Animais , Humanos , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismo , OsteogêneseRESUMO
Orf virus (Parapoxvirus ovis, ORFV) is a dermatotropic virus causing pustular dermatitis in small ruminants and humans. We analysed isolated human primary keratinocytes (KC) and dermal fibroblasts (FB) for cell death and virus replication by infection with a patient-derived ORFV isolate. ORFV infection was associated with rapid induction of cell death in KC allowing for considerable virus removal. Upon infection with ORFV, KC and FB harboured intracytoplasmic ORFV and showed viral protein presence; however, missing virus spread indicated an abortive infection. Upon ORFV exposure, KC but not FB secreted the pro-inflammatory cytokine interleukin (IL)-6. ORFV infection enhanced the frequency of KC expressing intercellular adhesion molecule (ICAM)-1 which was independent of IL-6. Interestingly, ORFV inhibited ICAM-1 up-regulation on infected but not on non-infected KC. Even interferon-γ, a potent inducer of ICAM-1, up-regulated ICAM-1 only on non-infected KC. Transfer of ORFV-free supernatant from infected to non-infected KC induced ICAM-1 on non-infected KC pointing to the involvement of soluble mediator(s). Similarly as in KC, in FB interference with ICAM-1 up-regulation by ORFV infection was also observed. In conclusion, we shed light on epidermal and dermal defense mechanisms to ORFV infection and point to a novel ICAM-1-related immune evasion mechanism of ORFV in human skin.
Assuntos
Ectima Contagioso/complicações , Fibroblastos/virologia , Molécula 1 de Adesão Intercelular/metabolismo , Queratinócitos/virologia , Vírus do Orf , Morte Celular , Humanos , Sistema Imunitário , Inflamação , Interferon gama/metabolismo , Interleucina-6/metabolismo , Microscopia de Contraste de Fase , Pele/citologia , Regulação para Cima , Replicação ViralRESUMO
Many members of the serine protease inhibitor (serpin) family are activated by glycosaminoglycans (GAGs). Visceral adipose tissue-derived serpin (vaspin), serpin A12 of the serpin family, and its target protease kallikrein 7 (KLK7) are heparin-binding proteins, and inhibition of KLK7 by vaspin is accelerated by heparin. However, the nature of GAG binding to vaspin is not known. Here, we measured vaspin binding of various glycosaminoglycans and low molecular weight heparins by microscale thermophoresis and analyzed acceleration of protease inhibition by these molecules. In addition, basic residues contributing to heparin binding and heparin activation were identified by a selective labeling approach. Together, these data show that vaspin binds heparin with high affinity (KD = 21 ± 2 nm) and that binding takes place at a basic patch on top of ß-sheet A and is different from other heparin-binding serpins. Mutation of basic residues decreased heparin binding and activation of vaspin. Similarly, reactive center loop insertion into sheet A decreased heparin binding because it disturbs the basic cluster. Finally, using vaspin-overexpressing keratinocyte cells, we show that a significant part of secreted vaspin is bound in the extracellular matrix on the cell surface. Together, basic residues of central ß-sheet A contribute to heparin binding and activation of vaspin. Thus, binding to GAGs in the extracellular matrix can direct and regulate vaspin interaction with target proteases or other proteins and may play an important role in the various beneficial functions of vaspin in different tissues.
Assuntos
Matriz Extracelular , Heparina , Queratinócitos/metabolismo , Serpinas , Sítios de Ligação , Linhagem Celular , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Heparina/química , Heparina/metabolismo , Humanos , Queratinócitos/citologia , Ligação Proteica , Estrutura Secundária de Proteína , Serpinas/química , Serpinas/metabolismoRESUMO
Obesity is associated with body fat gain and impaired glucose metabolism. Here, we identified both body fat gain in obesity and impaired glucose metabolism as two independent risk factors for increased serum levels of free fatty acids (FFAs). Since obesity is associated with increased and/or delayed resolution of inflammation observed in various chronic inflammatory diseases such as psoriasis, we investigated the impact of FFAs on human monocyte-derived and mouse bone marrow-derived dendritic cell (DCs) functions relevant for the pathogenesis of chronic inflammation. FFAs such as palmitic acid (PA) and oleic acid (OA) did not affect the pro-inflammatory immune response of DCs. In contrast, PA and OA sensitize DCs resulting in augmented secretion of TH1/TH17-instructive cytokines upon pro-inflammatory stimulation. Interestingly, obesity in mice worsened a TH1/TH17-driven psoriasis-like skin inflammation. Strong correlation of the amount of total FFA, PA, and OA in serum with the severity of skin inflammation points to a critical role of FFA in obesity-mediated exacerbation of skin inflammation. Our data suggest that increased levels of FFAs might be a predisposing factor promoting a TH1/TH17-mediated inflammation such as psoriasis in response to an inflammatory danger signal.
Assuntos
Citocinas/imunologia , Células Dendríticas/imunologia , Ácidos Graxos não Esterificados/sangue , Psoríase/imunologia , Células Th1/imunologia , Células Th17/imunologia , Imunidade Adaptativa , Adulto , Idoso , Animais , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Adulto JovemRESUMO
Impaired cross talk between keratinocytes (KCs) and immune cells is believed to contribute to the pathogenesis of chronic inflammatory skin diseases, such as psoriasis. We have previously identified KCs as a rich source of the serpin protease inhibitor vaspin (serpinA12), originally described as an adipokine in adipose tissue. Herein, we studied whether dysregulated vaspin expression in KCs contributes to the pathogenesis of psoriasis. We found vaspin expression to be closely associated to epidermal differentiation, with low levels in proliferating KCs and high levels in differentiated cells. Consistently, in human psoriasis and in a mouse model of a psoriasis-like skin inflammation, epidermal vaspin expression was significantly down-regulated. Down-regulation of vaspin in KCs resulted in decreased expression of differentiation-associated genes and up-regulation of interferon-inducible and inflammation-associated psoriasis signature genes. Vaspin was also shown to modulate the communication between KCs and inflammatory cells under co-culture conditions. A decrease in vaspin expression in KCs stimulated the secretion of tumor necrosis factor-α, IL-1ß, IL-6, IL-8, and monocyte chemoattractant protein-1 by co-cultured dendritic cells, macrophages, monocytes, and neutrophils. Consequently, the application of vaspin inhibited myeloid cell infiltration in a mouse model of a psoriasis-like skin inflammation. In conclusion, vaspin expression by maturing KCs modulates cutaneous immune responses and may be involved in the pathogenesis of psoriasis.
Assuntos
Anti-Inflamatórios/imunologia , Citocinas/imunologia , Regulação da Expressão Gênica , Queratinócitos/imunologia , Psoríase/imunologia , Serpinas/imunologia , Adulto , Idoso , Citocinas/metabolismo , Células Dendríticas/metabolismo , Regulação para Baixo , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Regulação para CimaRESUMO
The outcome of a cutaneous immune response is critically dependent upon the ability of dendritic cells (DC) to migrate from skin to the draining lymph nodes - a process that is influenced by the cutaneous tissue microenvironment. Here, the role of fibroblasts - a major component of the dermal microenvironment - on the migratory capacity of monocyte-derived DC (MoDC) was investigated in a 3D collagen I matrix. Indeed, dermal fibroblasts supported the migration of pre-activated MoDC through a 3D collagen I matrix. Activation of human MoDC resulted in the release of TNFα and IL-1ß that in turn stimulated MMP-1 (human collagenase) and PGE2 secretion by human dermal fibroblasts. Transmigration assays confirmed the importance of fibroblast-derived MMP-1 and PGE2 for the migration of MoDC through a 3D collagen I matrix. Finally, in mice initiation of inflammation by induction of an irritant contact dermatitis or a psoriasis-like skin inflammation, the expression of the PGE2 generating cox-2 and the mouse collagen I degrading enzyme matrix metalloproteinases (MMP)-13 was strongly up-regulated. Our study indicates that MoDC are able to instruct dermal fibroblasts resulting in enhanced migratory capability of MoDC, thus highlighting the role of a crosstalk of DC with their stromal microenvironment for the control of cutaneous immune responses.
Assuntos
Microambiente Celular/fisiologia , Células Dendríticas/citologia , Dinoprostona/metabolismo , Fibroblastos/fisiologia , Metaloproteinase 1 da Matriz/metabolismo , Aminoquinolinas/toxicidade , Animais , Técnicas de Cultura de Células , Movimento Celular , Células Cultivadas , Colágeno Tipo I , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Citocinas/farmacologia , Dermatite de Contato/etiologia , Dermatite de Contato/metabolismo , Indução Enzimática , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Imiquimode , Irritantes/toxicidade , Lipopolissacarídeos/toxicidade , Metaloproteinase 13 da Matriz/biossíntese , Metaloproteinase 13 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/efeitos dos fármacos , Cloreto de Picrila/toxicidade , Psoríase/induzido quimicamente , Psoríase/metabolismo , Células Estromais/fisiologiaRESUMO
Basigin (BSG) is a multifunctional glycoprotein that plays an important role in male reproduction since male knockout (KO) mice are sterile. The Bsg KO testis lacks elongated spermatids and mature spermatozoa, a phenotype similar to that of alpha-mannosidase IIx (MX) KO mice. MX regulates formation of N-acetylglucosamine (GlcNAc) terminated N-glycans that participate in germ cell-Sertoli cell adhesion. Results showed that Bsg KO spermatocytes displayed normal homologous chromosome synapsis and progression through meiosis. However, only punctate expression of the round spermatid marker SP-10 in the acrosomal granule of germ cells of Bsg KO mice was detected indicating that spermatogenesis in Bsg KO mice was arrested at the early round spermatid stages. We observed a large increase in the number of germ cells undergoing apoptosis in Bsg KO testes. Using lectin blotting, we determined that GlcNAc terminated N-glycans are linked to BSG. GlcNAc terminated N-glycans were significantly reduced in Bsg KO testes. These observations indicate that BSG may act as a germ cell-Sertoli cell attachment molecule. Loss of BSG significantly reduced adhesion between GC-2 and SF7 cells. Moreover, wild type testes showed strong expression of N-cadherin (CDH2) while expression was greatly reduced in the testes of Bsg KO mice. In addition, the integrity of the blood-testis barrier (BTB) was compromised in Bsg KO testes. In conclusion, although some Bsg KO spermatogonia can undergo normal progression to the spermatocyte stage, BSG-mediated germ cell-Sertoli cell interactions appear to be necessary for integrity of the BTB and spermatocyte progression to mature spermatozoa.
Assuntos
Basigina/fisiologia , Infertilidade Masculina/etiologia , Interações Espermatozoide-Óvulo , Acetilglucosamina/metabolismo , Animais , Basigina/análise , Basigina/genética , Barreira Hematotesticular , Adesão Celular , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , EspermatogêneseRESUMO
The cell adhesion molecule Thy-1 (CD90) mediates the adhesion of melanoma cells to activated human endothelial cells (EC) via the interaction with the αvß3-integrin on the tumor cells in vitro. Here, we report a strong expression of Thy-1 on both blood vessel and lymphatic EC in melanoma and melanoma metastases. Vascular endothelial growth factor and tumor necrosis factor-α were identified as inducers of Thy-1 expression on EC in vitro. The physiological role of Thy-1 for lymphogenic and hematogenic metastasis of melanoma cells was substantiated in an experimental metastasis model using B16/F10 melanoma cells. Mice lacking Thy-1 showed markedly diminished experimental lung metastasis after injection of B16/F10 melanoma cells compared to wild-type littermate controls. In addition, on generation of a primary subcutaneous tumor, metastasis to regional lymph nodes was clearly reduced in Thy-1(-/-) mice. However, Thy-1 deletion did not affect subcutaneous primary tumor growth, tumor-induced recruitment of inflammatory cells or T cells, angiogenesis, or T-cell activation. In conclusion, Thy-1 contributes to metastasis of melanoma cells by mechanisms likely involving a Thy-1-mediated adhesion of melanoma cells to EC.
Assuntos
Melanoma/secundário , Antígenos Thy-1/fisiologia , Animais , Adesão Celular/fisiologia , Células Endoteliais/metabolismo , Endotélio Linfático/metabolismo , Endotélio Vascular/metabolismo , Humanos , Neoplasias Pulmonares/secundário , Metástase Linfática , Melanoma/metabolismo , Melanoma/patologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Melanoma Experimental/secundário , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante de Neoplasias , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/secundário , Transplante Heterólogo , Fator de Necrose Tumoral alfa/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
Leukocyte recruitment in response to inflammatory signals is governed, in part, by binding to Thy-1 (CD90) on activated endothelial cells (EC). In this study, we characterized the adhesion G-protein coupled receptor CD97, present on peripheral myeloid cells, as a novel interacting partner for Thy-1. CD97 was upregulated on polymorphonuclear cells (PMNC) of patients with psoriasis. In psoriatic skin lesions, CD97(+) myeloid cells colocalized with Thy-1(+) EC of small vessels in microabscesses, suggesting an interaction between CD97 and Thy-1 that was further examined by adhesion and protein-binding assays. PMNC and cell lines stably overexpressing CD97 adhered specifically to Thy-1(+)-activated human dermal EC, Thy-1(+) CHO cells, and immobilized Thy-1 protein. Binding of the CD97(+) CHO clones correlated with their CD97 expression level. Soluble CD97 bound specifically to immobilized Thy-1 protein, as well as Thy-1(+)-activated EC and CHO cells. In all assays, cellular adhesion or protein binding was blocked partially by CD97 and Thy-1-blocking mAb. Our data suggested that CD97 interacts via its stalk with Thy-1 because mAb directed to the stalk of CD97 showed stronger blocking compared with mAb to its epidermal growth factor-like domains, and binding was calcium independent. Moreover, soluble CD97 without the stalk and soluble EMR2, containing highly homologous epidermal growth factor-like domains but a different stalk, failed to bind. In summary, binding of leukocytes to activated endothelium mediated by the interaction of CD97 with Thy-1 is involved in firm adhesion of PMNC during inflammation and may play a role in the regulation of leukocyte trafficking to inflammatory sites.
Assuntos
Antígenos CD/metabolismo , Células Endoteliais/metabolismo , Antígenos Thy-1/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Adesão Celular , Feminino , Humanos , Migração e Rolagem de Leucócitos , Leucócitos/metabolismo , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Ligação Proteica/imunologia , Psoríase/imunologia , Receptores Acoplados a Proteínas GRESUMO
The excessive accumulation of adipose tissue in obesity is associated with multiple inflammatory dermatological diseases. Chemerin, a chemoattractant adipokine, dependent on proteolytical activation, is highly expressed in skin. Different proteases have been reported to activate prochemerin, but none is inherently expressed in human skin. In the present study, we identified a tissue-specific protease and investigated the underlying mechanism of activation at the molecular level. We characterized human KLK7 (kallikrein 7) as a prochemerin processing protease in vitro converting prochemerin into active chemerinF(156). The activating truncation by the protease might trigger a structural rearrangement leading to an increased affinity of chemerin to CMKLR1 (chemokine-like receptor 1). Molecular modelling and experimental data suggest an underlying ionic interaction in prochemerin C-terminal domains. These findings provide a general molecular basis for the necessity of C-terminal processing of prochemerin. Moreover, immunohistochemistry was used to investigate prochemerin, KLK7 and the recently identified KLK7 inhibitor vaspin expression in human skin biopsies, and distinct co-localization in psoriatic biopsies was observed. On the basis of these results, it is hypothesized that KLK7 activity may contribute to the development of psoriatic lesions as a consequence of excessive chemerin activation and impaired protease activity regulation by vaspin. Therefore this interaction represents an interesting target for psoriasis therapy and treatment of other obesity-related diseases.
Assuntos
Quimiocinas/química , Quimiocinas/metabolismo , Calicreínas/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Proteólise , Sequência de Aminoácidos , Quimiocinas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Calicreínas/genética , Modelos Moleculares , Dados de Sequência Molecular , Fragmentos de Peptídeos/genética , Precursores de Proteínas/genética , Psoríase/enzimologia , Psoríase/metabolismo , Receptores de Quimiocinas/metabolismoRESUMO
Effective tissue response to infection and injury essentially relies on the fine-tuned induction and subsequent resolution of inflammation. Recent research highlighted multiple functions of dermal white adipose tissue (dWAT) beyond its traditional role as an energy reservoir. However, in contrast to other fat depots, there are only limited data about putative immune-regulatory functions of dWAT. Therefore, we investigated the impact of dWAT in the control of an acute skin inflammation. Skin inflammation triggers the activation of dWAT. In turn, soluble mediators of activated dWAT stimulate the expression of numerous genes controlling skin inflammation, including the T helper 2 cell cytokines Il4 and Il13, in myeloid cells in vitro. Consistently, myeloid cells isolated from inflamed skin showed a significant upregulation of Il-4/13 expression compared with those isolated from healthy skin. Mechanistically, we demonstrate that IL-33 released from activated dWAT is responsible for IL-4/13 stimulation in myeloid cells. Interestingly, obesity attenuates IL-33 secretion in dWAT during inflammation, resulting in decreased Il-4 and Il-13 expressions in myeloid cells. Our data reveal an IL-33-IL-4/13 signaling cascade initiated from dWAT in a T helper 2-independent context of inflammation that may contribute to limitation of inflammation. This cascade seems to be disturbed in individuals with obesity with prolonged inflammation.
RESUMO
Nutrition, together with weight gain, alcohol consumption, physical activity, and other factors, is a risk factors for chronic inflammatory diseases [...].
Assuntos
Obesidade , Aumento de Peso , Humanos , Pele , Fatores de Risco , Estado NutricionalRESUMO
Obesity and high abdominal fat mass are risk factors for developing the chronic inflammatory skin disease psoriasis. They are associated with increased incidence, prevalence and severity of the disease. A positive effect of weight loss on psoriasis activity has been shown in several studies. Obesity-related factors such as the dysregulation of glucose and lipid metabolism, the activation of adipose tissue and resultant persistent low-grade inflammation have been discussed as links of obesity and inflammatory diseases. Recently, we demonstrated a critical role of free fatty acids (FFAs) in obesity-mediated exacerbation of psoriatic skin inflammation in both mice and humans. In the present study, we translated these findings into a therapeutic intervention. An open-label study focusing on the dietary reduction of FFAs was conducted in patients with mild-to-moderate plaque psoriasis, and disease severity and serum markers of inflammation were analyzed. Here, we show that such a dietary intervention improves psoriatic disease activity independently of weight loss. Diet-related metabolic changes, such as a reduction in saturated free fatty acids (SFAs), may thus be more important than weight loss itself. Moreover, dietary intervention inhibited the overall pro-inflammatory activation status in patients, as shown by analysis of serum inflammatory parameters using the Olink platform. From our pilot study, we conclude that dietary intervention focusing on SFA reduction has the capacity to reduce disease activity and general inflammatory status in psoriasis patients.
Assuntos
Ácidos Graxos não Esterificados , Psoríase , Humanos , Gorduras na Dieta , Ácidos Graxos , Inflamação , Obesidade/complicações , Obesidade/metabolismo , Projetos Piloto , Psoríase/complicações , Redução de PesoRESUMO
Human Thy-1 (CD90) has been shown to mediate adhesion of inflammatory cells to activated microvascular endothelial cells via interaction with Mac-1 (CD11b/CD18) in vitro. Since there are no data showing the physiological relevance of Thy-1 for the recruitment of inflammatory cells in vivo, different inflammation models were investigated in Thy-1-deficient mice and littermate controls. In thioglycollate-induced peritonitis, the number of neutrophils and monocytes was significantly diminished in Thy-1-deficient mice. During acute lung inflammation, the extravasation of eosinophils and monocytes into the lung was significantly reduced in Thy-1-deficient mice. Moreover, during chronic lung inflammation, the influx of eosinophils and monocytes was also strongly decreased. These effects were independent of Thy-1 expression on T cells, as shown by the transplantation of WT BM into the Thy-1-deficient mice. In spite of the strong Thy-1 expression on T cells in the chimeric mice, the extravasation of the inflammatory cells in these mice was significantly diminished, compared to control mice. Finally, the altered number and composition of infiltrating leukocytes in Thy-1-deficient mice modified the chemokine/cytokine and protease expression at the site of inflammation. In conclusion, Thy-1 is involved in the control of inflammatory cell recruitment and, thus, also in conditioning the inflammatory microenvironment.
Assuntos
Inflamação/imunologia , Leucócitos/imunologia , Antígenos Thy-1/metabolismo , Animais , Adesão Celular/imunologia , Movimento Celular/imunologia , Quimiocinas/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/patologia , Eosinófilos/imunologia , Eosinófilos/patologia , Humanos , Técnicas In Vitro , Inflamação/patologia , Interleucinas/metabolismo , Leucócitos/patologia , Leucócitos/fisiologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Peptídeo Hidrolases/metabolismo , Peritonite/imunologia , Peritonite/patologia , Peritonite/fisiopatologia , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/fisiopatologia , Linfócitos T/imunologia , Linfócitos T/patologia , Antígenos Thy-1/genética , Quimeras de Transplante/imunologiaRESUMO
The initiation of immune responses is associated with the maturation of dendritic cells (DCs) and their migration to draining lymph nodes. En route activated DCs encounter cells of the tissue microenvironment, such as fibroblasts. Because we have shown that DCs interact with fibroblasts during immune responses, we studied the impact of skin fibroblasts on human monocyte-derived DC function and subsequent human T-cell (TC) differentiation. We show that fibroblasts support interleukin-23 (IL-23) secretion from DCs preactivated by lipopolysaccharide (DC(act)) compared with lipopolysaccharide-activated DCs alone. The underlying complex feedback-loop mechanism involves IL-1ß/tumor necrosis factor-α (from DC(act)), which stimulate fibroblasts prostaglandin E(2) production. Prostaglandin E(2), in turn, acts on DC(act) and increases their IL-23 release. Furthermore, fibroblast-stimulated DC(act) are far superior to DC(act) alone, in promoting the expansion of Th17 cells in a Cox-2-, IL-23-dependent manner. Using CD4(+)CD45RO(+) memory TCs and CD4(+)CD45RA(+) naive TCs, we showed that fibroblasts induce a phenotype of DC(act) that promotes the expansion of Th17 cells. Moreover, in psoriasis, a prototypic immune response in which the importance of IL-23/Th17 is known, high expression of Cox-2 in fibroblasts was observed. In conclusion, skin fibroblasts are involved in regulation of IL-23 production in DCs and, as a result, of Th17 expansion.
Assuntos
Células Dendríticas/citologia , Fibroblastos/citologia , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Linfócitos T/citologia , Células Cultivadas , Técnicas de Cocultura , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Células Dendríticas/metabolismo , Dinoprostona/metabolismo , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-23/genética , Monócitos/citologia , Monócitos/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/citologia , Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para CimaRESUMO
Psoriasis is an inflammatory skin disease often associated with obesity. The anti-inflammatory adipokine vaspin, a suggested serine proteinase inhibitor of the serpin family, is discussed as a new link between inflammation and obesity. Here, we demonstrate that - different from healthy controls - vaspin serum levels in patients with psoriasis were body mass index independent. Moreover, we could identify keratinocytes as the major source of vaspin in skin. Vaspin expression in lesional psoriatic skin was reduced compared with uninvolved skin as shown by immunohistochemistry and RT-PCR. In aggregate, we report on the cellular source of vaspin in skin and its expression in psoriasis.
Assuntos
Obesidade/complicações , Obesidade/metabolismo , Psoríase/complicações , Psoríase/metabolismo , Serpinas/metabolismo , Sequência de Bases , Índice de Massa Corporal , Estudos de Casos e Controles , Expressão Gênica , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Queratinócitos/metabolismo , Obesidade/sangue , Obesidade/genética , Obesidade/patologia , Psoríase/sangue , Psoríase/genética , Psoríase/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serpinas/sangue , Serpinas/genética , Pele/metabolismo , Pele/patologiaRESUMO
Psoriasis is a chronic inflammatory disease of the skin and joints associated with several comorbidities such as arthritis, diabetes mellitus and metabolic syndrome, including obesity, hypertension and dyslipidaemia, Crohn's disease, uveitis and psychiatric and psychological diseases. Psoriasis has been described as an independent risk factor for cardiovascular diseases and thus patients with psoriasis should be monitored for the development of cardiovascular disease or metabolic syndrome. However, there is mounting evidence that psoriasis also affects the development of osteoporosis, an important metabolic disease with enormous clinical and socioeconomic impact. At present, there are still controversial opinions about the role of psoriasis in osteoporosis. A more in depth analysis of this phenomenon is of great importance for affected patients since, until now, bone metabolism is not routinely examined in psoriatic patients, which might have important long-term consequences for patients and the health system. In the present review, we summarize current knowledge on the impact of psoriatic inflammation on bone metabolism and osteoporosis.