RESUMO
Cytotoxic activity is a hallmark of the immunopathogenesis in human cutaneous leishmaniasis (CL). In this study, we identified accumulation of CD4+ granzyme B producing T cells with increased cytotoxic capacity in CL lesions. These cells showed enhanced expression of activating NK receptors (NKG2D and NKG2C), diminished expression of inhibitory NKG2A, along with the upregulation of the senescence marker CD57. Notably, CD4+ T cells freshly isolated from CL lesions demonstrated remarkable capacity to mediate NL-like bystander cytolysis. Phenotypic analyses revealed that lesional CD4+ T cells are mainly composed of late-differentiated effector (CD27-CD45RA-) and terminally differentiated (senescent) TEMRA (CD27-CD45RA+) subsets. Interestingly, the TEMRA CD4+ T cells exhibited higher expression of granzyme B and CD107a. Collectively, our results provide the first evidence that senescent cytotoxic CD4+ T cells may support the skin pathology of human cutaneous leishmaniasis and, together with our previous findings, support the notion that multiple subsets of cytotoxic senescent cells may be involved in inducing the skin lesions in these patients.
Assuntos
Linfócitos T CD4-Positivos , Senescência Celular , Leishmaniose Cutânea , Pele , Humanos , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Leishmaniose Cutânea/parasitologia , Senescência Celular/imunologia , Linfócitos T CD4-Positivos/imunologia , Pele/imunologia , Pele/patologia , Pele/parasitologia , Granzimas/metabolismo , Citotoxicidade Imunológica , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Efeito Espectador/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto JovemRESUMO
Leprosy is a neglected contagious disease that causes physical disability and episodes of inflammation, called leprosy reactions. There are currently no consolidated laboratory markers that can predict or confirm the diagnosis of leprosy reactions, negatively impacting the progression of the disease. The aim of this study was to analyze the behavior of inflammatory biomarkers in a population of patients with multibacillary leprosy. This prospective study in a northeastern capital involved 67 new cases of multibacillary leprosy, assessing inflammatory biomarkers at diagnosis. Histopathology, qPCR, slit skin smear microscopy, and laboratory tests, including CRP-albumin, neutrophil-lymphocyte, lymphocyte-monocyte, platelet-lymphocyte ratios, and systemic immune-inflammation index, were conducted. Statistical analysis utilized Stata version 16.0®, employing Chi-square, Kruskal-Wallis, and Poisson regression (5% significance). The population, mainly young brown men with low socioeconomic status, borderline leprosy, and and degree of physical disability one, saw 19.4% experiencing leprosy reactions. Standard multibacillary multidrug therapy was administered to all. Ratios and index values exceeding medians were prevalent (46.3-47.8%). Assessing biological markers against leprosy reactions revealed a positive relation between reactions and lymphocyte-platelet ratio (p = 0.05) and a positive trend with the systemic immune-inflammation index (p = 0.06). Patients with reactions were 1.3 times more likely to exhibit an elevated lymphocyte-platelet ratio. The lymphocyte-platelet ratio emerged as a potential indicator for recognizing leprosy reactions. Further research is essential to validate these findings, aiming for earlier detection of leprosy reactions.
Assuntos
Biomarcadores , Plaquetas , Hanseníase Multibacilar , Linfócitos , Humanos , Masculino , Feminino , Adulto , Biomarcadores/sangue , Estudos Prospectivos , Pessoa de Meia-Idade , Plaquetas/imunologia , Linfócitos/imunologia , Hanseníase Multibacilar/diagnóstico , Hanseníase Multibacilar/imunologia , Adulto Jovem , Contagem de Plaquetas , Adolescente , Idoso , Contagem de Linfócitos , Inflamação/diagnóstico , Inflamação/imunologia , Inflamação/sangue , Pele/patologia , Pele/imunologia , Pele/microbiologia , Hansenostáticos/uso terapêuticoRESUMO
Interleukin (IL) 17 is a proinflammatory cytokine belonging to a structurally related group of cytokines known as the IL-17 family. It has been profoundly studied for its contribution to the pathology of autoimmune diseases. However, it also plays an important role in homeostasis and the defense against extracellular bacteria and fungi. IL-17 is important for epithelial barriers, including the skin, where some of its cellular targets reside. Most of the research work on IL-17 has focused on its effects in the skin within the context of autoimmune diseases or sterile inflammation, despite also having impact on other skin conditions. In recent years, studies on the role of IL-17 in the defense against skin pathogens and in the maintenance of skin homeostasis mediated by the microbiota have grown in importance. Here we review and discuss the cumulative evidence regarding the main contribution of IL-17 in the maintenance of skin integrity as well as its protective or pathogenic effects during some skin infections.
Assuntos
Interleucina-17 , Pele , Animais , Humanos , Homeostase , Interleucina-17/imunologia , Interleucina-17/metabolismo , Pele/imunologia , Pele/microbiologia , Pele/patologia , Dermatopatias Infecciosas/imunologia , Dermatopatias Infecciosas/microbiologia , Doenças Autoimunes/imunologiaRESUMO
Obesity is a global pandemic associated with several comorbidities, such as cardiovascular diseases and type 2 diabetes. It is also a predisposing factor for infectious diseases, increasing mortality rates. Moreover, diet-induced obesity can cause metabolic fluctuations that affect macrophage differentiation in various organs. In this sense, we investigated how bone marrow-derived macrophages and tissue-resident macrophages in the skin, which have been differentiated in a host with metabolic syndrome and with previous inflammatory burden, respond to Leishmania major infection. Our findings suggest that bone marrow-derived macrophages from obese C57BL/6 mice, even when cultivated in vitro with inflammatory stimuli, are more susceptible to L. major. These macrophages produce less tumor necrosing factor (TNF) and nitric oxide (NO) and show higher arginase activity. Furthermore, obese mice infected with an intermediate dose of L. major in the skin had more severe lesions when analyzed for ulceration, diameter, thickness, and parasite burden. The increase in lesion severity in obese mice was associated with a higher frequency of tissue-resident macrophages, which are less efficient in killing parasites. We also used CCR2-/- mice, which predominantly have tissue-resident macrophages, and found that lesion resolution was delayed in association with CCR2 deficiency. Additionally, obesity potentiated tissue damage, resulting in higher frequency of tissue-resident macrophages. Our results demonstrate that obesity can alter macrophage responses to infection, leading to increased susceptibility to L. major and more severe cutaneous leishmaniasis. These findings may have important implications for managing obesity-related infections and the development of new therapies for cutaneous leishmaniasis.
Assuntos
Leishmania major , Leishmaniose Cutânea , Macrófagos , Camundongos Endogâmicos C57BL , Obesidade , Animais , Obesidade/imunologia , Obesidade/patologia , Obesidade/complicações , Leishmania major/imunologia , Macrófagos/imunologia , Macrófagos/parasitologia , Macrófagos/patologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Leishmaniose Cutânea/parasitologia , Camundongos , Receptores CCR2/metabolismo , Pele/parasitologia , Pele/patologia , Pele/imunologia , Camundongos KnockoutRESUMO
Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus, and chronic skin colonization by Staphylococcus aureus. To understand the inflammatory status in AD, we investigated the inflammasome complex, that activates ASC (Apoptosis-associated speck-like protein containing a CARD), caspase-1 and GSDMD (gasdermin-D), and production of IL-1ß and IL-18. We aimed to evaluate the expression of the inflammasome pathway in the skin of adults with AD. Thirty patients with moderate to severe AD and 20 healthy controls were enrolled in the study. We performed the analysis of the inflammasome components NLRP1, NLRP3, AIM-2, IL-1ß, IL-18, Caspase-1, ASC, GSDMD, and CD68 expression (macrophage marker) by immunohistochemistry and immunofluorescence. The main findings included increased expression of NLRP3, NLRP1 and AIM-2 at dermal level of severe AD; augmented IL-18 and IL-1ß expression at epidermis of moderate and severe patients, and in the dermis of severe AD; augmented expression of ASC, caspase-1 and GSDMD in both epidermis and dermis of moderate and severe AD. We detected positive correlation between caspase-1, GSDMD and IL-1ß (epidermis) and caspase-1 (dermis) and AD severity; NLRP3, AIM-2 and IL-1ß, and NLRP3 with IL-18 in the epidermis; ASC, GSDMD and IL-1ß, and NLRP3, AIM-2, caspase-1, and IL-18 in the dermis. We also evidenced the presence of CD68+ macrophages secreting GSDMD, ASC and IL-1ß in moderate and severe AD. Cutaneous macrophages, early detected in moderate AD, have its role in the disease inflammatory mechanisms. Our study indicates a canonical activation pathway of inflammasomes, reinforced by the chronic status of inflammation in AD. The analysis of the inflammasome complex evidenced an imbalance in its regulation, with increased expression of the evaluated components, which is remarkably in severe AD, emphasizing its relevance as potential disease biomarkers and targets for immunomodulatory interventions.
Assuntos
Proteínas Adaptadoras de Sinalização CARD , Caspase 1 , Dermatite Atópica , Inflamassomos , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Estudos de Casos e Controles , Caspase 1/metabolismo , Molécula CD68 , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Proteínas de Ligação a DNA , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Gasderminas , Inflamassomos/metabolismo , Inflamassomos/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Índice de Gravidade de Doença , Pele/patologia , Pele/imunologia , Pele/metabolismoRESUMO
Diisopentyl phthalate (DiPeP) is primarily used as a plasticizer or additive within the production of polyvinyl chloride (PVC), and has many additional industrial applications. Its metabolites were recently found in urinary samples of pregnant women; thus, this substance is of concern as relates to human exposure. Depending upon the nature of the alcohol used in its synthesis, DiPeP may exist either as a mixture consisting of several branched positional isomers, or as a single defined structure. This article investigates the skin sensitization potential and immunomodulatory effects of DiPeP CAS No. 84777-06-0, which is currently marketed and classified as a UVCB substance, by in silico and in vitro methods. Our findings showed an immunomodulatory effect for DiPeP in LPS-induced THP-1 activation assay (increased CD54 expression). In silico predictions using QSAR TOOLBOX 4.5, ToxTree, and VEGA did not identify DiPeP, in the form of a discrete compound, as a skin sensitizer. The keratinocyte activation (Key Event 2 (KE2) of the adverse outcome pathway (AOP) for skin sensitization) was evaluated by two different test methods (HaCaT assay and RHE assay), and results were discordant. While the HaCaT assay showed that DiPeP can activate keratinocytes (increased levels of IL-6, IL-8, IL-1α, and ILA gene expression), in the RHE assay, DiPeP slightly increased IL-6 release. Although inconclusive for KE2, the role of DiPeP in KE3 (dendritic cell activation) was demonstrated by the increased levels of CD54 and IL-8 and TNF-α in THP-1 cells (THP-1 activation assay). Altogether, findings were inconclusive regarding the skin sensitization potential of the UVCB DiPeP-disagreeing with the results of DiPeP in the form of discrete compound (skin sensitizer by the LLNA assay). Additional studies are needed to elucidate the differences between DiPeP isomer forms, and to better understand the applicability domains of non-animal methods in identifying skin sensitization hazards of UVCB substances.
Assuntos
Simulação por Computador , Queratinócitos , Ácidos Ftálicos , Humanos , Queratinócitos/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Células HaCaT , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Relação Quantitativa Estrutura-Atividade , Plastificantes/toxicidade , Células THP-1 , Molécula 1 de Adesão Intercelular/metabolismo , Molécula 1 de Adesão Intercelular/genética , Linhagem CelularRESUMO
The relationship between psoriasis severity and psychological stress has been described in several studies. However, the mechanism by which chronic stress exacerbates psoriasis is not completely understood. This study aimed at investigating whether chronic psychological stress can aggravate psoriasis-like skin inflammation. Mice were subjected to a restraint stress model and topically treated with imiquimod (IMQ). Differentiated human keratinocytes were treated with high epinephrine levels and IMQ in vitro. Stress aggravated macroscopic features and the increase in epidermal thickness induced by IMQ in mouse skin. The increase in NF-κB and IL-17A expression induced by IMQ was potentiated by chronic stress in mouse skin. The skin of stressed mice treated with IMQ showed higher levels of ß2-adrenergic receptors (ß2-AR). In human keratinocytes, high epinephrine levels exacerbated the increase in the levels of ß2-AR and IL-17A induced by IMQ. ß-AR antagonist reversed the effects of chronic stress in IMQ-induced inflammation both in vivo and in vitro. In conclusion, stress-stimulated overactivation of the ß2-AR and NF-κB pathways potentiates a Th1/Th17 profile leading to an exacerbation of psoriasis.
Assuntos
Imiquimode , Interleucina-17 , Queratinócitos , NF-kappa B , Psoríase , Receptores Adrenérgicos beta 2 , Transdução de Sinais , Estresse Psicológico , Animais , Humanos , Masculino , Camundongos , Modelos Animais de Doenças , Epinefrina , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-17/metabolismo , Queratinócitos/metabolismo , Queratinócitos/imunologia , NF-kappa B/metabolismo , Psoríase/imunologia , Psoríase/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Pele/patologia , Pele/imunologia , Pele/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/imunologia , Células Th1/imunologia , Células Th17/imunologiaRESUMO
Innate lymphoid cells (ILCs) are the most recently described group of lymphoid subpopulations. These tissue-resident cells display a heterogeneity resembling that observed on different groups of T cells, hence their categorization as cytotoxic NK cells and helper ILCs type 1, 2 and 3. Each one of these groups is highly diverse and expresses different markers in a context-dependent manner. Type 2 innate lymphoid cells (ILC2s) are activated in response to helminth parasites and regulate the immune response. They are involved in the etiology of diseases associated with allergic responses as well as in the maintenance of tissue homeostasis. Markers associated with their identification differ depending on the tissue and model used, making the study and understanding of these cells a cumbersome task. This review compiles evidence for the heterogeneity of ILC2s as well as discussion and analyses of molecular markers associated with their identity, function, tissue-dependent expression, and how these markers contribute to the interaction of ILC2s with specific microenvironments to maintain homeostasis or respond to pathogenic challenges.
Assuntos
Antígenos de Diferenciação/análise , Subpopulações de Linfócitos/imunologia , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/patologia , Animais , Citocinas/metabolismo , Helmintíase/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Homeostase , Humanos , Imunofenotipagem , Inflamação , Intestinos/imunologia , Pulmão/imunologia , Subpopulações de Linfócitos/química , Camundongos , Nutrientes , Especificidade de Órgãos , Proteínas Proto-Oncogênicas c-kit/imunologia , Receptores de Superfície Celular/imunologia , Pele/imunologia , Fator de Células-Tronco/imunologiaRESUMO
The induction of trained immunity represents an emerging concept defined as the ability of innate immune cells to acquire a memory phenotype, which is a typical hallmark of the adaptive response. Key points modulated during the establishment of trained immunity include epigenetic, metabolic and functional changes in different innate-immune and non-immune cells. Regarding to epigenetic changes, it has been described that long non-coding RNAs (LncRNAs) act as molecular scaffolds to allow the assembly of chromatin-remodeling complexes that catalyze epigenetic changes on chromatin. On the other hand, relevant metabolic changes that occur during this process include increased glycolytic rate and the accumulation of metabolites from the tricarboxylic acid (TCA) cycle, which subsequently regulate the activity of histone-modifying enzymes that ultimately drive epigenetic changes. Functional consequences of established trained immunity include enhanced cytokine production, increased antigen presentation and augmented antimicrobial responses. In this article, we will discuss the current knowledge regarding the ability of different cell subsets to acquire a trained immune phenotype and the molecular mechanisms involved in triggering such a response. This knowledge will be helpful for the development of broad-spectrum therapies against infectious diseases based on the modulation of epigenetic and metabolic cues regulating the development of trained immunity.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunidade Celular , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Imunidade Adaptativa/fisiologia , Animais , Vacina BCG/imunologia , Brônquios/citologia , Brônquios/imunologia , Citocinas/fisiologia , Metabolismo Energético , Epigênese Genética , Células Epiteliais/imunologia , Trato Gastrointestinal/citologia , Trato Gastrointestinal/imunologia , Células-Tronco Hematopoéticas/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Imunidade Celular/genética , Imunidade Celular/fisiologia , Imunidade Inata/genética , Imunidade Inata/fisiologia , Memória Imunológica/genética , Memória Imunológica/fisiologia , Linfócitos/imunologia , Camundongos , Células Mieloides/imunologia , NAD/fisiologia , Pele/citologia , Pele/imunologiaRESUMO
The keratinocyte (KC) is the main functional and structural component of the epidermis, the most external layer of the skin that is highly specialized in defense against external agents, prevention of leakage of body fluids and retention of internal water within the cells. Altered epidermal barrier and aberrant KC differentiation are involved in the pathophysiology of several skin diseases, such as atopic dermatitis (AD). AD is a chronic inflammatory disease characterized by cutaneous and systemic immune dysregulation and skin microbiota dysbiosis. Nevertheless, the pathological mechanisms of this complex disease remain largely unknown. In this review, we summarize current knowledge about the participation of the KC in different aspects of the AD. We provide an overview of the genetic predisposing and environmental factors, inflammatory molecules and signaling pathways of the KC that participate in the physiopathology of the AD. We also analyze the link among the KC, the microbiota and the inflammatory response underlying acute and chronic skin AD lesions.
Assuntos
Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Queratinócitos/metabolismo , Alelos , Animais , Biomarcadores , Terapia Combinada , Dermatite Atópica/patologia , Dermatite Atópica/terapia , Gerenciamento Clínico , Progressão da Doença , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Interações entre Hospedeiro e Microrganismos , Humanos , Imunidade Inata , Queratinócitos/imunologia , Microbiota , Pele/imunologia , Pele/metabolismo , Pele/patologia , Fenômenos Fisiológicos da PeleRESUMO
The treatment of multibacillary cases of leprosy with multidrug therapy (MDT) comprises 12 doses of a combination of rifampicin, dapsone and clofazimine. Previous studies have described the immunological phenotypic pattern in skin lesions in multibacillary patients. Here, we evaluated the effect of MDT on skin cell phenotype and on the Mycobacterium leprae-specific immune response. An analysis of skin cell phenotype demonstrated a significant decrease in MRS1 (SR-A), CXCL10 (IP-10) and IFNG (IFN-γ) gene and protein expression after MDT release. Patients were randomized according to whether they experienced a reduction in bacillary load after MDT. A reduction in CXCL10 (IP-10) in sera was associated with the absence of a reduction in the bacillary load at release. Although IFN-γ production in response to M. leprae was not affected by MDT, CXCL10 (IP-10) levels in response to M. leprae increased in cells from patients who experienced a reduction in bacillary load after treatment. Together, our results suggest that CXCL10 (IP-10) may be a good marker for monitoring treatment efficacy in multibacillary patients.
Assuntos
Quimiocina CXCL10/sangue , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Pele/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carga Bacteriana/efeitos dos fármacos , Biomarcadores/sangue , Quimiocina CXCL10/imunologia , Quimioterapia Combinada , Feminino , Humanos , Hansenostáticos/administração & dosagem , Hanseníase/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Pele/microbiologia , Pele/patologia , Resultado do Tratamento , Adulto JovemAssuntos
Ectima/imunologia , Doenças da Imunodeficiência Primária/diagnóstico , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/isolamento & purificação , Sepse/imunologia , Pele/patologia , Ectima/diagnóstico , Ectima/patologia , Evolução Fatal , Gangrena , Humanos , Lactente , Quinases Associadas a Receptores de Interleucina-1 , Masculino , Doenças da Imunodeficiência Primária/complicações , Infecções por Pseudomonas/diagnóstico , Infecções por Pseudomonas/patologia , Sepse/diagnóstico , Sepse/patologia , Pele/imunologia , Pele/microbiologiaRESUMO
Cystatins are natural inhibitors of cysteine peptidases that are found practically in all living organisms. CaneCPI-5 is a sugarcane cystatin with inhibitory activity against human cathepsins B, K and L, which are cysteine proteases highly expressed in a variety of pathological conditions, usually marked by persistent inflammation and processing of the extracellular matrix. This work evaluated the effects of daily administration of the recombinant cystatin CaneCPI-5 [0.01, 0.1 or 1.0 µg in 10 µL of Phosphate-Buffered Saline (PBS)] on the inflammatory, angiogenic and fibrogenic components during chronic inflammatory response induced by subcutaneous sponge implants. The anti-inflammatory effect of treatment with CaneCPI-5 was confirmed by reduction of the levels of the pro-inflammatory mediators TNF-α, CXCL1 and CCL2/JE/MCP-1, as well as the activity of the myeloperoxidase and n-acetyl-ß-D-glucosaminidase. Treatment with CaneCPI-5 promoted angiogenesis in the implants, increasing the production of cytokines VEGF and FGF and the formation of new blood vessels. Finally, the administration of the recombinant cystatin favored the production of the pro-fibrogenic cytokine TGF-ß1 and collagen deposition next to the implants. Together, these results show the potential therapeutic application of CaneCPI-5 as an anti-inflammatory agent, capable of favoring angiogenesis and fibrogenesis processes, necessary for tissue repair.
Assuntos
Anti-Inflamatórios/uso terapêutico , Colágeno/metabolismo , Cistatinas/uso terapêutico , Corpos Estranhos/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas de Plantas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Cistatinas/genética , Cistatinas/farmacologia , Citocinas/imunologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Corpos Estranhos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas de Plantas/genética , Proteínas de Plantas/farmacologia , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Saccharum , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Tampões de Gaze Cirúrgicos , CamundongosRESUMO
Leishmaniases are diseases caused by several Leishmania species, and many factors contribute to the development of the infection. Because the adaptive immune response does not fully explain the outcome of Leishmania infection and considering that the initial events are crucial in the establishment of the infection, we investigated one of the growth factors, the insulin-like growth factor-I (IGF-I), found in circulation and produced by different cells including macrophages and present in the skin where the parasite is inoculated. Here, we review the role of IGF-I in leishmaniasis experimental models and human patients. IGF-I induces the growth of different Leishmania species in vitro and alters the disease outcome increasing the parasite load and lesion size, especially in L. major- and L. amazonensis-infected mouse leishmaniasis. IGF-I affects the parasite interacting with the IGF-I receptor present on Leishmania. During Leishmania-macrophage interaction, IGF-I acts on the arginine metabolic pathway, resulting in polyamine production both in macrophages and Leishmania. IGF-I and cytokines interact with reciprocal influences on their expression. IL-4 is a hallmark of susceptibility to L. major in murine leishmaniasis, but we observed that IGF-I operates astoundingly as an effector element of the IL-4. Approaching human leishmaniasis, patients with mucosal, disseminated, and visceral diseases presented surprisingly low IGF-I serum levels, suggesting diverse effects than parasite growth. We observed that low IGF-I levels might contribute to the inflammatory response persistence and delayed lesion healing in human cutaneous leishmaniasis and the anemia development in visceral leishmaniasis. We must highlight the complexity of infection revealed depending on the Leishmania species and the parasite's developmental stages. Because IGF-I exerts pleiotropic effects on the biology of interaction and disease pathogenesis, IGF-I turns up as an attractive tool to explore biological and pathogenic processes underlying infection development. IGF-I pleiotropic effects open further the possibility of approaching IGF-I as a therapeutical target.
Assuntos
Interações Hospedeiro-Parasita/imunologia , Fator de Crescimento Insulin-Like I/metabolismo , Leishmania/imunologia , Leishmaniose/imunologia , Animais , Modelos Animais de Doenças , Humanos , Leishmaniose/parasitologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Pele/imunologia , Pele/metabolismo , Pele/parasitologiaRESUMO
Macrophages play important roles in the innate and acquired immune responses against Leishmania parasites. Depending on the subset and activation status, macrophages may eliminate intracellular parasites; however, these host cells also can offer a safe environment for Leishmania replication. In this sense, the fate of the parasite may be influenced by the phenotype of the infected macrophage, linked to the subtype of classically activated (M1) or alternatively activated (M2) macrophages. In the present study, M1 and M2 macrophage subsets were analyzed by double-staining immunohistochemistry in skin biopsies from patients with American cutaneous leishmaniasis (ACL) caused by L. (L.) amazonensis, L. (V.) braziliensis, L. (V.) panamensis ,and L. (L.) infantum chagasi. High number of M1 macrophages was detected in nonulcerated cutaneous leishmaniasis (NUCL) caused by L. (L.) infantum chagasi (M1 = 112 ± 12, M2 = 43 ± 12 cells/mm2). On the other side, high density of M2 macrophages was observed in the skin lesions of patients with anergic diffuse cutaneous leishmaniasis (ADCL) (M1 = 195 ± 25, M2 = 616 ± 114), followed by cases of localized cutaneous leishmaniasis (LCL) caused by L. (L.) amazonensis (M1 = 97 ± 24, M2 = 219 ± 29), L. (V.) panamensis (M1 = 71 ± 14, M2 = 164 ± 14), and L. (V.) braziliensis (M1 = 50 ± 13, M2 = 53 ± 10); however, low density of M2 macrophages was observed in NUCL. The data presented herein show the polarization of macrophages in skin lesions caused by different Leishmania species that may be related with the outcome of the disease.
Assuntos
Leishmania/imunologia , Leishmaniose Cutânea/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , Pele/parasitologia , Biópsia , Humanos , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Macrófagos/parasitologia , Pele/imunologia , Pele/patologiaRESUMO
Desmogleins are involved in cell adhesion conferring structural skin integrity. However, their role in inflammation has been barely studied, and whether desmoglein-4 modulates psoriasis lesions is completely unknown. In this study, we assessed the impact of desmoglein-4 deficiency on the severity of imiquimod (IMQ)-induced skin inflammation and psoriasiform lesions. To this end, desmoglein-4-/- Oncins France Colony A (OFA) with Sprague-Dawley (SD) genetic background were used. Additionally, human RNA-Seq datasets from psoriasis (PSO), atopic dermatitis (AD), and a healthy cohort were analyzed to obtain a desmosome gene expression overview. OFA rats displayed an intense skin inflammation while SD showed only mild inflammatory changes after IMQ treatment. We found that IMQ treatment increased CD3+ T cells in skin from both OFA and SD, being higher in desmoglein-4-deficient rats. In-depth transcriptomic analysis determined that PSO displayed twofold less DSG4 expression than healthy samples while both, PSO and AD showed more than three-fold change expression of DSG3 and DSC2 genes. Although underlying mechanisms are still unknown, these results suggest that the lack of desmoglein-4 may contribute to immune-mediated skin disease progression, promoting leukocyte recruitment to skin. Although further research is needed, targeting desmoglein-4 could have a potential impact on designing new biomarkers for skin diseases.
Assuntos
Desmogleínas/deficiência , Psoríase/metabolismo , Pele/metabolismo , Animais , Complexo CD3/metabolismo , Estudos de Casos e Controles , Quimiotaxia de Leucócito , Desmogleínas/genética , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Imiquimode , Mediadores da Inflamação/metabolismo , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Ratos Sprague-Dawley , Ratos Transgênicos , Pele/imunologia , Pele/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , RatosRESUMO
Dengue is a worldwide expanding threat caused by dengue virus (DENV) infection. To date, no specific treatment or effective vaccine is available. Antibodies produced by plasma cells (PCs) might be involved concomitantly in protection and severe dengue immunopathology. Although a massive appearance of PCs has been reported during acute DENV infection in humans, this response has been poorly characterized. Here, we show the dynamic of PC generation in immune-competent mice cutaneously inoculated with DENV compared with two control experimental groups: mice inoculated with inactivated DENV or with PBS. We found that PC numbers increased significantly in the skin-draining lymph node (DLN), peaking at day 10 and abruptly decreasing by day 14 after DENV inoculation. Class-switched IgG+ PCs appeared from day 7 and dominated the response, while in contrast, the frequency of IgM+ PCs decreased from day 7 onwards. Even though the kinetic of the response was similar between DENV- and iDENV-inoculated mice, the intensity of the response was significantly different. Interestingly, we demonstrated a similar PC response to virus antigens (E and prM) by ELISPOT. In situ characterization showed that PCs were distributed in the medullary cords and in close proximity to germinal centers (GCs), suggesting both an extrafollicular and a GC origin. Proliferating PCs (Ki-67+) were found as early as 3-day postinoculation, and in-depth analysis showed that these PCs were in active phases of cell cycle during the kinetic. Finally, we found a progressive appearance of high-affinity neutralizing DENV-specific IgG further supporting GC involvement. Of note, these antibodies seem to be highly cross-reactive, as a large proportion recognizes Zika virus (ZIKV). The strong PC response to skin-inoculated DENV in this work resembles the findings already described in humans. We consider that this study contributes to the understanding of the in vivo biology of the humoral immune response to DENV in an immunocompetent murine model.
Assuntos
Vírus da Dengue/imunologia , Dengue/imunologia , Plasmócitos/imunologia , Animais , Anticorpos Neutralizantes/análise , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/análise , Anticorpos Antivirais/metabolismo , Reações Cruzadas , Dengue/patologia , Dengue/virologia , Modelos Animais de Doenças , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Masculino , Camundongos , Plasmócitos/metabolismo , Pele/imunologia , Pele/patologia , Pele/virologia , Organismos Livres de Patógenos Específicos , Zika virus/imunologiaRESUMO
BACKGROUND: Cytokines and growth factors involved in the tissue inflammatory process influence the outcome of Leishmania infection. Insulin-like growth factor (IGF-I) constitutively present in the skin may participate in the inflammatory process and parasite-host interaction. Previous work has shown that preincubation of Leishmania (Leishmania) amazonensis with recombinant IGF-I induces accelerated lesion development. However, in human cutaneous leishmaniasis (CL) pathogenesis, it is more relevant to the persistent inflammatory process than progressive parasite proliferation. In this context, we aimed to investigate whether IGF-I was present in the CL lesions and if this factor may influence the lesions' development acting on parasite growth and/or on the inflammatory/healing process. Methodology. Fifty-one CL patients' skin lesion samples from endemic area of L. (Viannia) braziliensis infection were submitted to histopathological analysis and searched for Leishmania and IGF-I expression by immunohistochemistry. RESULTS: In human CL lesions, IGF-I was observed preferentially in the late lesion (more than 90 days), and the percentage of positive area for IGF-I was positively correlated with duration of illness (r = 0.42, P < 0.05). IGF-I was highly expressed in the inflammatory infiltrate of CL lesions from patients evolving with good response to therapy (2.8% ± 2.1%; median = 2.1%; n = 18) than poor responders (1.3% ± 1.1%; median: 1.05%; n = 6; P < 0.05). CONCLUSIONS: It is the first time that IGF-I was detected in lesions of infectious cutaneous disease, specifically in American tegumentary leishmaniasis. IGF-I was related to chronicity and good response to treatment. We may relate this finding to the efficient anti-inflammatory response and the known action of IGF-I in wound repair. The present data highlight the importance of searching nonspecific factors besides adaptive immune elements in the study of leishmaniasis' pathogenesis.
Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Leishmania braziliensis/imunologia , Leishmaniose Cutânea/imunologia , Pele/patologia , Adolescente , Adulto , Animais , Brasil , Feminino , Interações Hospedeiro-Parasita/imunologia , Humanos , Leishmania braziliensis/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Masculino , Pessoa de Meia-Idade , Pele/imunologia , Pele/microbiologia , Cicatrização/imunologia , Adulto JovemRESUMO
Leprosy is an infectious disease that remains endemic in approximately 100 developing countries, where about 200,000 new cases are diagnosed each year. Moreover, multibacillary leprosy, the most contagious form of the disease, has been detected at continuously higher rates among Brazilian elderly people. Due to the so-called immunosenescence, characterized by several alterations in the quality of the immune response during aging, this group is more susceptible to infectious diseases. In view of such data, the purpose of our work was to investigate if age-related alterations in the immune response could influence the pathogenesis of leprosy. As such, we studied 87 individuals, 62 newly diagnosed and untreated leprosy patients distributed according to the age range and to the clinical forms of the disease and 25 healthy volunteers, who were studied as controls. The frequency of senescent and memory CD8+ leukocytes was assessed by immunofluorescence of biopsies from cutaneous lesions, while the serum levels of IgG anti-CMV antibodies were analyzed by chemiluminescence and the gene expression of T cell receptors' inhibitors by RT-qPCR. We noted an accumulation of memory CD8+ T lymphocytes, as well as reduced CD8+CD28+ cell expression in skin lesions from elderly patients, when compared to younger people. Alterations in LAG3 and PDCD1 gene expression in cutaneous lesions of young MB patients were also observed, when compared to elderly patients. Such data suggest that the age-related alterations of T lymphocyte subsets can facilitate the onset of leprosy in elderly patients, not to mention other chronic inflammatory diseases.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Senescência Celular/imunologia , Memória Imunológica , Imunossenescência/imunologia , Hanseníase/imunologia , Mycobacterium leprae , Dermatopatias/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Antígenos CD/genética , Estudos de Casos e Controles , Citomegalovirus/imunologia , Feminino , Expressão Gênica , Humanos , Imunoglobulina G/sangue , Hanseníase/sangue , Hanseníase/microbiologia , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Pele/imunologia , Pele/patologia , Dermatopatias/sangue , Dermatopatias/microbiologia , Dermatopatias/patologia , Adulto Jovem , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Patients infected by Leishmania braziliensis develop debilitating skin lesions. The role of inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in both CD4+ and CD8+ T cell subsets. Moreover, PDL-1/PDL-2 ligands were increased on skin macrophages compared to healthy controls. The proportions PD1+, but not TIM-3 or CTLA-4 expressing T cells in the circulation were positively correlated with those in the lesions of the same patients, suggesting that PD-1 may regulate T cell function equally in both compartments. Blocking PD-1 signaling in circulating T cells enhanced their proliferative capacity and IFN-γ production, but not TNF-α secretion in response to L. braziliensis recall antigen challenge in vitro. While we previously showed a significant correlation between the accumulation of senescent CD8+CD45RA+CD27- T cells in the circulation and skin lesion size in the patients, there was no such correlation between the extent of PD-1 expression by circulating on T cells and the magnitude of skin lesions suggesting that exhausted-like T cells may not contribute to the cutaneous immunopathology. Nevertheless, we identified exhausted-like T cells in both skin lesions and in the blood. Targeting this population by PD-1 blockade may improve T cell function and thus accelerate parasite clearance that would reduce the cutaneous pathology in cutaneous leishmaniasis.