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Objective: Dendritic cells (DCs) are important players in immunity against pathogens, but overactive DCs have been implicated in autoimmune diseases, like lupus, in which a paucity of targeted therapies remains. Recent research shows that DCs upregulate their immunometabolism when activating. We explored whether modulating fatty acid (FA) metabolism needed for oxidative phosphorylation can affect the activation of two main DC subsets. Material and methods: Sorted murine plasmacytoid DCs (pDCs) and conventional DCs (cDCs), generated in FLT3-L medium, were treated with etomoxir, an inhibitor of FA oxidation, or TOFA, an inhibitor of FA synthesis, then stimulated with TLR9 agonist CpGA. Surface activation markers and viability were analyzed by flow cytometry, cytokine, and chemokine production and were measured by ELISA. Results: Modulation of FA metabolism suppressed the upregulation of costimulatory molecules and the production of proinflammatory cytokine IL-6 and type I Interferon-dependent chemokine CXCL10 by both subsets of DCs, without affecting DC viability, neither of resting DCs or upon activation. Etomoxir inhibited pDCs at lower doses than cDCs, suggesting that pDCs may be more susceptible to FA metabolic modulation. Conclusions: Both cDCs, the primary antigen presenting cell, and pDCs, the primary type I IFN producer, exhibit a suppressed ability to activate but normal viability when their FA metabolism is inhibited by etomoxir or TOFA. Our findings indicate that FA metabolism plays an important role in the activation of both pDCs and cDCs and suggest that its modulation is an exploitable therapeutic target to suppress DC activation in inflammation or autoimmunity.
Assuntos
Células Dendríticas/imunologia , Compostos de Epóxi/farmacologia , Ácidos Graxos/imunologia , Furanos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Citocinas/imunologia , Células Dendríticas/citologia , Camundongos , Receptor Toll-Like 9/imunologiaRESUMO
STAT2 is a central component of the ISGF3 transcriptional complex downstream of type I interferon (IFN-I) signaling. The significance of in vivo IFN-I/STAT1 signals in cDCs is well-established in the generation of antitumor cytotoxic T cell (CTL) responses. However, the role of STAT2 has remained elusive. Here, we report a clinical correlation between cDC markers and STAT2 associated with better survival in human metastatic melanoma. In a murine tumor transplantation model, targeted Stat2 deletion in CD11c+cDCs enhanced tumor growth unaffected by IFNß therapy. Furthermore, STAT2 was essential for both, the activation of CD8a+cDCs and CD11b+cDCs and antigen cross-presentation in vivo for the generation of robust T cell killing response. In contrast, STAT2 in CD11c+cDCs was dispensable for stimulating an antigen-specific humoral response, which was impaired in global Stat2 deficient mice. Thus, our studies indicate that STAT2 in cDCs is critical in host IFN-I signals by sculpting CTL responses against tumors.
Assuntos
Formação de Anticorpos , Células Dendríticas , Animais , Apresentação Cruzada , Células Dendríticas/metabolismo , Camundongos , Fator de Transcrição STAT2/genética , Transdução de SinaisRESUMO
Infections are considered important environmental triggers of autoimmunity and can contribute to autoimmune disease onset and severity. Nucleic acids and the complexes that they form with proteins-including chromatin and ribonucleoproteins-are the main autoantigens in the autoimmune disease systemic lupus erythematosus (SLE). How these nuclear molecules become available to the immune system for recognition, presentation, and targeting is an area of research where complexities remain to be disentangled. In this review, we discuss how bacterial infections participate in the exposure of nuclear autoantigens to the immune system in SLE. Infections can instigate pro-inflammatory cell death programs including pyroptosis and NETosis, induce extracellular release of host nuclear autoantigens, and promote their recognition in an immunogenic context by activating the innate and adaptive immune systems. Moreover, bacterial infections can release bacterial DNA associated with other bacterial molecules, complexes that can elicit autoimmunity by acting as innate stimuli of pattern recognition receptors and activating autoreactive B cells through molecular mimicry. Recent studies have highlighted SLE disease activity-associated alterations of the gut commensals and the expansion of pathobionts that can contribute to chronic exposure to extracellular nuclear autoantigens. A novel field in the study of autoimmunity is the contribution of bacterial biofilms to the pathogenesis of autoimmunity. Biofilms are multicellular communities of bacteria that promote colonization during chronic infections. We review the very recent literature highlighting a role for bacterial biofilms, and their major components, amyloid/DNA complexes, in the generation of anti-nuclear autoantibodies and their ability to stimulate the autoreactive immune response. The best studied bacterial amyloid is curli, produced by enteric bacteria that commonly cause infections in SLE patients, including Escherichia coli and Salmonella spps. Evidence suggests that curli/DNA complexes can trigger autoimmunity by acting as danger signals, molecular mimickers, and microbial chaperones of nucleic acids.
Assuntos
Autoantígenos/imunologia , Infecções Bacterianas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Autoimunidade , Infecções Bacterianas/epidemiologia , Biofilmes , Morte Celular , Núcleo Celular/imunologia , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Microbiota , Mimetismo MolecularRESUMO
Gradations in skin color are a consequence of differing amounts of melanin and their varying distribution. Although many darkly pigmented skin lesions are melanocytic and can be attributed to melanin content, the color of a black lesion can also be due to blood, necrotic tissue, or exogenous pigment. The source, pattern, and distribution of the color in black lesions usually offer important insight into its etiology. This contribution reviews conditions that can take on a black color, discussing the cause of the hue and any additional impact sun exposure may have.
Assuntos
Hiperpigmentação/diagnóstico , Hiperpigmentação/etiologia , Lúpus Eritematoso Discoide/diagnóstico , Melanoma/diagnóstico , Nevo Azul/diagnóstico , Neoplasias Cutâneas/diagnóstico , Acantose Nigricans/diagnóstico , Acantose Nigricans/etiologia , Acantose Nigricans/terapia , Calciofilaxia/diagnóstico , Calciofilaxia/tratamento farmacológico , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/patologia , Dermatomicoses/complicações , Dermatomicoses/diagnóstico , Diagnóstico Diferencial , Humanos , Hiperpigmentação/terapia , Ceratose Seborreica/diagnóstico , Lúpus Eritematoso Discoide/tratamento farmacológico , Melanoma/etiologia , Melanoma/terapia , Mucormicose/complicações , Mucormicose/diagnóstico , Mucormicose/terapia , Mucosa , Doenças da Unha/diagnóstico , Nevo Azul/cirurgia , Nevo Fusocelular/diagnóstico , Nevo Fusocelular/patologia , Ocronose/diagnóstico , Ocronose/etiologia , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico , Prognóstico , Dermatopatias Papuloescamosas/diagnóstico , Dermatopatias Papuloescamosas/etiologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , TatuagemRESUMO
White diseases are a heterogenous group characterized by hypopigmentation or depigmentation. Skin and eye color are determined by the number and size of melanosomes present. Melanin is produced by melanosomes in the melanocytes present within the epidermis of the skin, uvea, and retinal pigmented epithelium (RPE). Conditions altering the number of melanocytes or concentration of melanin result in a lack of pigmentation, appearing as "white diseases" ranging from the well-known albinism and vitiligo to more esoteric white hand syndrome and Degos disease.
Assuntos
Hipopigmentação/diagnóstico , Hipopigmentação/etiologia , Albinismo/diagnóstico , Albinismo/etiologia , Albinismo/terapia , Cor , Cosméticos/efeitos adversos , Diagnóstico Diferencial , Humanos , Hipopigmentação/patologia , Hipopigmentação/terapia , Inflamação/complicações , Líquen Escleroso e Atrófico/diagnóstico , Líquen Escleroso e Atrófico/etiologia , Líquen Escleroso e Atrófico/patologia , Líquen Escleroso e Atrófico/terapia , Papulose Atrófica Maligna/diagnóstico , Papulose Atrófica Maligna/etiologia , Papulose Atrófica Maligna/patologia , Mucosa , Doenças da Unha/etiologia , Nevo com Halo/diagnóstico , Nevo com Halo/etiologia , Nevo com Halo/patologia , Pitiríase Liquenoide/diagnóstico , Pitiríase Liquenoide/etiologia , Pitiríase Liquenoide/terapia , Prognóstico , Preparações Clareadoras de Pele/efeitos adversos , Tinha Versicolor/diagnóstico , Tinha Versicolor/tratamento farmacológico , Tinha Versicolor/etiologia , Vibração/efeitos adversos , Vitiligo/diagnóstico , Vitiligo/etiologia , Vitiligo/terapia , Síndrome de Waardenburg/diagnóstico , Síndrome de Waardenburg/etiologiaRESUMO
BACKGROUND: Chronic pruritus is defined as itch lasting for greater than six weeks. Pruritus is a burdensome manifestation of several internal and external disease states with a significant impact on quality of life. Dupilumab has shown promise in treating a number of conditions including atopic dermatitis (AD) and asthma. Its success in reducing pruritus in AD has generated interest regarding its potential application in other pruritic conditions, such as chronic pruritus of unknown origin, uremic pruritus, and pruigo nodularis. METHODS: In this retrospective analysis, we present a series of 20 recalcitrant pruritus patients seen at a tertiary center treated with off-label dupilumab at standard AD dosing. RESULTS: Dupilumab was successful at reducing itch in all treated patients, leading to complete resolution in 12/20 patients and an overall mean NRSi reduction of 7.55. Dupilumab was well tolerated with no significant adverse effects. CONCLUSIONS: Our case series suggests dupilumab may be a safe and efficacious therapeutic option in several pruritic conditions and demonstrates the need for further studies to better ascertain its place in the pruritus treatment armamentarium.
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Attenuating the innate immunity activation could ameliorate inflammation and disease in settings such as transplant rejection or autoimmunity. Recently, a pivotal role for metabolic re-programming in TLR-induced dendritic cell (DC) activation has emerged. Ethyl pyruvate (EP), a pyruvate derivative, possesses anti-inflammatory properties in vitro and in animal models of disease. However, its effects on DCs remain elusive. We found that EP attenuated LPS-induced activation of murine GM-CSF bone marrow-derived dendritic cells (DCs) in vitro, reducing pro-inflammatory cytokine and IL-10 production, costimulatory molecule and MHC expression, the type I Interferon (IFN-I) response, the LPS-induced cell death, and the ability of DCs to stimulate allogeneic T cells. DC activation induced by TLR7 and TLR9 ligands was also suppressed by EP in vitro. Finally, EP decreased TLR-induced activation stimulated in vivo in conventional DCs and inflammatory monocytes. Investigating EP mechanisms, we found that EP decreased glycolysis and mitochondrial respiration, upon and in absence of TLR stimulation, by reducing ERK, AKT, and nitric oxide (NO) activation. These results indicate that EP inhibits most of the DC biological responses to TLR triggering, altering the metabolic reprogramming necessary for DC activation.