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1.
Nat Genet ; 54(5): 637-648, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35513723

RESUMO

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of natural killer (NK) cells where the underlying genetic mechanisms are incompletely understood. In the present study, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations were enriched at highly conserved residues, mutually exclusive of STAT3 mutations and associated with gene expression programs that resembled normal CD16dim/CD56bright NK cells. Mechanistically, the mutations resulted in ligand-biased chemokine receptor signaling, with decreased internalization of the G-protein-coupled receptor (GPCR) for CCL22, CCR4, via impaired ß-arrestin recruitment. This resulted in increased cell chemotaxis in vitro, bidirectional crosstalk with the hematopoietic microenvironment and enhanced NK cell proliferation in vivo in transgenic human IL-15 mice. Somatic CCL22 mutations illustrate a unique mechanism of tumor formation in which gain-of-function chemokine mutations promote tumorigenesis by biased GPCR signaling and dysregulation of microenvironmental crosstalk.


Assuntos
Quimiocina CCL22 , Células Matadoras Naturais , Transtornos Linfoproliferativos , Animais , Quimiocina CCL22/genética , Células Matadoras Naturais/patologia , Ativação Linfocitária , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/metabolismo , Transtornos Linfoproliferativos/patologia , Camundongos , Mutação
3.
PLoS One ; 17(2): e0263997, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35176085

RESUMO

Long noncoding RNA (LncRNA) is a new type of regulatory RNA. LncRNA HOX antisense intergenic RNA (HOTAIR), as an oncogene in non-small cell lung cancer (NSCLC), is one of the key determinants of tumor progression. However, its possible molecular mechanism and the immunomodulatory pathway involved in NSCLC are still unclear. This study aims to explore whether HOTAIR promotes proliferation, migration and invasion of the NSCLC cells by inhibiting the expression of C-C Motif Chemokine Ligand 22 (CCL22). We collected 30 clinical samples of cancer and adjacent normal tissues from the patients with NSCLC, using real-time quantitative polymerase chain reaction (RT-qPCR) to detect the LncRNA HOTAIR and CCL22 mRNA expression in tissues. Immunohistochemistry was used to detect the protein expression of CCL22 in cancer and adjacent normal tissues. Cell experiments were conducted to verify that LncRNA HOTAIR regulates the expression of CCL22 and participates in the progress of NSCLC. The antisense oligonucleotide (ASO) probe interfering with LncRNA HOTAIR and the interference fragment of CCL22 (si-CCL22) were constructed. A549 cells were co-transfected with ASO-HOTAIR and si-CCL22. We used RT-qPCR to detect the expression of LncRNA HOTAIR and CCL22 mRNA in the cells, enzyme-linked immunosorbent assay (ELISA) used to detect the CCL22 protein level in the cell supernatant. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was applied to detect cell proliferation, the Flow cytometry to detect cell apoptosis. Finally, the Transwell test was utilized to detect cell migration and invasion. In conclusion, this study suggests that HOTAIR may promote proliferation, migration and invasion of the NSCLC cells by inhibiting CCL22 expression, which may play a key role in NSCLC cell immunity.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Proliferação de Células , Quimiocina CCL22/metabolismo , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quimiocina CCL22/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Prognóstico , Células Tumorais Cultivadas
4.
Int J Mol Sci ; 23(3)2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35163802

RESUMO

There are several open questions to be answered regarding the pathophysiology of the development of preeclampsia (PE). Numerous factors are involved in its genesis, such as defective placentation, vascular impairment, and an altered immune response. The activation of the adaptive and innate immune system represents an immunologic, particularity during PE. Proinflammatory cytokines are predominantly produced, whereas immune regulatory and immune suppressive factors are diminished in PE. In the present study, we focused on the recruitment of regulatory T cells (Tregs) which are key players in processes mediating immune tolerance. To identify Tregs in the decidua, an immunohistochemical staining of FoxP3 of 32 PE and 34 control placentas was performed. A clearly reduced number of FoxP3-positive cells in the decidua of preeclamptic women could be shown in our analysis (p = 0.036). Furthermore, CCL22, a well-known Treg chemoattractant, was immunohistochemically evaluated. Interestingly, CCL22 expression was increased at the maternal-fetal interface in PE-affected pregnancies (psyncytiotrophoblast = 0.035, pdecidua = 0.004). Therefore, the hypothesis that Tregs undergo apoptosis at the materno-fetal interface during PE was generated, and verified by FoxP3/TUNEL (TdT-mediated dUTP-biotin nick end labeling) staining. Galectin-2 (Gal-2), a member of the family of carbohydrate-binding proteins, which is known to be downregulated during PE, seems to play a pivotal role in T cell apoptosis. By performing a cell culture experiment with isolated Tregs, we could identify Gal-2 as a factor that seems to prevent the apoptosis of Tregs. Our findings point to a cascade of apoptosis of Tregs at the materno-fetal interface during PE. Gal-2 might be a potential therapeutic target in PE to regulate immune tolerance.


Assuntos
Decídua/imunologia , Regulação para Baixo , Galectina 2/metabolismo , Pré-Eclâmpsia/metabolismo , Linfócitos T Reguladores/citologia , Adolescente , Adulto , Apoptose , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL22/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Idade Materna , Gravidez , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Adulto Jovem
5.
BMC Pulm Med ; 22(1): 29, 2022 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-35000593

RESUMO

BACKGROUND: Asthma is a heterogeneous disease and different phenotypes based on clinical parameters have been identified. However, the molecular subgroups of asthma defined by gene expression profiles of induced sputum have been rarely reported. METHODS: We re-analyzed the asthma transcriptional profiles of the dataset of GSE45111. A deep bioinformatics analysis was performed. We classified 47 asthma cases into different subgroups using unsupervised consensus clustering analysis. Clinical features of the subgroups were characterized, and their biological function and immune status were analyzed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and single sample Gene Set Enrichment Analysis (ssGSEA). Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network were performed to identify key gene modules and hub genes. RESULTS: Unsupervised consensus clustering of gene expression profiles in asthma identified two distinct subgroups (Cluster I/II), which were significantly associated with eosinophilic asthma (EA) and paucigranulocytic asthma (PGA). The differentially expressed genes (DEGs) between the two subgroups were primarily enriched in immune response regulation and signal transduction. The ssGSEA suggested the different immune infiltration and function scores between the two clusters. The WGCNA and PPI analysis identified three hub genes: THBS1, CCL22 and CCR7. ROC analysis further suggested that the three hub genes had a good ability to differentiate the Cluster I from the Cluster II. CONCLUSIONS: Based on the gene expression profiles of the induced sputum, we identified two asthma subgroups, which revealed different clinical characteristics, gene expression patterns, biological functions and immune status. The transcriptional classification confirms the molecular heterogeneity of asthma and provides a framework for more in-depth research on the mechanisms of asthma.


Assuntos
Asma/genética , Quimiocina CCL22/genética , Análise por Conglomerados , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Humanos , Inflamação/genética , Receptores CCR7/genética , Trombospondina 1/genética
6.
PLoS Pathog ; 18(1): e1010200, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35025968

RESUMO

The Epstein-Barr Virus (EBV) is involved in the etiology of multiple hematologic and epithelial human cancers. EBV+ tumors employ multiple immune escape mechanisms, including the recruitment of immunosuppressive regulatory T cells (Treg). Here, we show some EBV+ tumor cells express high levels of the chemokines CCL17 and CCL22 both in vitro and in vivo and that this expression mirrors the expression levels of expression of the EBV LMP1 gene in vitro. Patient samples from lymphoblastic (Hodgkin lymphoma) and epithelial (nasopharyngeal carcinoma; NPC) EBV+ tumors revealed CCL17 and CCL22 expression of both tumor cell-intrinsic and -extrinsic origin, depending on tumor type. NPCs grown as mouse xenografts likewise showed both mechanisms of chemokine production. Single cell RNA-sequencing revealed in vivo tumor cell-intrinsic CCL17 and CCL22 expression combined with expression from infiltrating classical resident and migratory dendritic cells in a CT26 colon cancer mouse tumor engineered to express LMP1. These data suggest that EBV-driven tumors employ dual mechanisms for CCL17 and CCL22 production. Importantly, both in vitro and in vivo Treg migration was effectively blocked by a novel, small molecule antagonist of CCR4, CCR4-351. Antagonism of the CCR4 receptor may thus be an effective means of activating the immune response against a wide spectrum of EBV+ tumors.


Assuntos
Quimiocina CCL17/imunologia , Quimiocina CCL22/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Neoplasias/imunologia , Neoplasias/virologia , Linfócitos T Reguladores/imunologia , Animais , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Xenoenxertos , Doença de Hodgkin/imunologia , Doença de Hodgkin/virologia , Humanos , Camundongos , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/virologia
7.
Proc Natl Acad Sci U S A ; 119(4)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35046040

RESUMO

Inflammatory pain, such as hypersensitivity resulting from surgical tissue injury, occurs as a result of interactions between the immune and nervous systems with the orchestrated recruitment and activation of tissue-resident and circulating immune cells to the site of injury. Our previous studies identified a central role for Ly6Clow myeloid cells in the pathogenesis of postoperative pain. We now show that the chemokines CCL17 and CCL22, with their cognate receptor CCR4, are key mediators of this response. Both chemokines are up-regulated early after tissue injury by skin-resident dendritic and Langerhans cells to act on peripheral sensory neurons that express CCR4. CCL22, and to a lesser extent CCL17, elicit acute mechanical and thermal hypersensitivity when administered subcutaneously; this response abrogated by pharmacological blockade or genetic silencing of CCR4. Electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice showed that CCL22 was able to directly activate neurons and enhance their excitability after injury. These responses were blocked using C 021 and small interfering RNA (siRNA)-targeting CCR4. Finally, our data show that acute postoperative pain is significantly reduced in mice lacking CCR4, wild-type animals treated with CCR4 antagonist/siRNA, as well as transgenic mice depleted of dendritic cells. Together, these results suggest an essential role for the peripheral CCL17/22:CCR4 axis in the genesis of inflammatory pain via direct communication between skin-resident dendritic cells and sensory neurons, opening therapeutic avenues for its control.


Assuntos
Células de Langerhans/metabolismo , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/metabolismo , Receptores CCR4/metabolismo , Células Receptoras Sensoriais/metabolismo , Potenciais de Ação , Animais , Biomarcadores , Quimiocina CCL17/genética , Quimiocina CCL17/metabolismo , Quimiocina CCL22/genética , Quimiocina CCL22/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Células de Langerhans/imunologia , Camundongos , Dor Pós-Operatória/diagnóstico , Transdução de Sinais
8.
J Cutan Pathol ; 49(3): 261-273, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34687561

RESUMO

Currently, there are no curative treatment options for mycosis fungoides (MF) and Sézary syndrome (SS) other than stem cell transplant. Understanding the interplay between tumor cells and tumor microenvironment could aid in the development of new therapies. Tumor-associated macrophages (TAMs) mostly have M2 phenotype that promotes tumor progression. This study investigated CD68+ and CD163+ TAMs as well as CD163/CD68 ratio in skin lesions from different stages of MF, large-plaque parapsoriasis, and SS. Moreover, we analyzed serum levels of sCD163 and CCL22 in correlation with TAMs count and CD163/CD68 ratio. CD68+ and CD163+ TAMs count significantly increased as the disease progressed. CD163/CD68 ratio was highest at MF tumor stage and SS indicating M2 polarization with disease progression. Significant positive correlations were detected between serum levels of sCD163 and CCL22 and CD68+ and CD163+ TAMs count and CD163/CD68 ratio. We concluded that TAMs play an important role in MF progression. High CD163/CD68 ratio in tumor stage MF and SS indicates M2 polarization of TAMs with tumor progression. CD163/CD68 ratio should be considered in assessing TAMs rather than total TAMs count. Also, sCD163 and CCL22 serum levels reflect M2 load and thus could be used as markers to assess disease progression.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Quimiocina CCL22/sangue , Micose Fungoide/patologia , Receptores de Superfície Celular/análise , Síndrome de Sézary/patologia , Macrófagos Associados a Tumor/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pele/patologia
9.
Anticancer Drugs ; 33(2): 149-157, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34657098

RESUMO

Recently, cytokine-induced killer (CIK) cells have been shown to possess effective cytotoxic activity against some tumor cells both in vitro and in clinical research. Furthermore, dendritic cell-activated CIK (DC-CIK) cells display significantly increased antitumor activity compared to unstimulated CIK cells. Study findings indicate DC cells can secrete chemokine C-C motif ligand 17 (CCL17) and chemokine C-C motif ligand 22 (CCL22) with a common receptor molecule, C-C chemokine receptor type-4(CCR4). CCL17 and CCL22 levels were measured by ELISA from CIK cell culture supernatants and the expression of CCR4 on CIK and DC-CIK cells was analyzed by flow cytometry. Through Migration and Killing assays, further analyzed the effects of the altered expression levels of CCR4 on the chemotactic ability and the tumor-killing efficiency of CIK cells. We found markedly increased CCL17 and CCL22 in supernatants of DC-CIK co-cultures. Similarly, the expression of CCR4 was also increased on CIK cells in these co-cultures. Further, the stimulation of CCL17 and CCL22 increased expression of the CCR4 and enhanced the migratory capacity and antitumor efficacy of CIK cells. Simultaneously, similar effects had achieved by transfecting the CCR4 gene into CIK cells. DC cells may promote the expression of CCR4 on CIK cells by secreting CCL17 and CCL22, thereby promoting infiltration of DC-CIK cells into the tumor microenvironment, and exerting stronger antitumor activity than CIK cells.


Assuntos
Quimiocina CCL17/metabolismo , Quimiocina CCL22/metabolismo , Células Matadoras Induzidas por Citocinas/metabolismo , Receptores CCR4/biossíntese , Movimento Celular/fisiologia , Células Dendríticas , Humanos , Ligantes
10.
Bioengineered ; 12(2): 11277-11287, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34874224

RESUMO

A great many microRNAs (miRNAs) have been reported to play different roles in human cancers, including gastric cancer (GC). However, the specific character of miR-23a-3p in GC has not been elucidated. This study was to explore the function of miR-23a-3p in GC. The results manifested that miR-23a-3p was down-regulated in GC and patients with reduced miR-23a-3p had poor prognosis. Functional experiments assured that elevated miR-23a-3p refrained GC proliferation, invasion, migration, PIK3/Akt phosphorylation and apoptosis, while knockdown miR-23a-3p accelerated the growth of GC. Double luciferase report experiments manifested that miR-23a-3p targeted CCL22 expression. Functional rescue experiments affirmed that the repression of elevated miR-23a-3p on GC was reversed by simultaneous augmented CCL22. In vivo, elevated miR-23a-3p restrained the volume and tumor of GC and reduced the expression of CCL22 and phosphorylated PIK3/Akt, while knockdown miR-23a-3p motivated tumor growth. In conclusion, the results of this study indicate that miR-23a-3p plays a repressive role in GC, and affects the progression of GC via down-regulating CCL22 and blocking PI3K/AKT signal transduction pathway, which may offer a new molecular target for clinical treatment of GC.


Assuntos
Quimiocina CCL22/metabolismo , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Progressão da Doença , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Transdução de Sinais/genética
11.
mBio ; 12(6): e0159121, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34781732

RESUMO

Toxoplasma gondii is an intracellular protozoan pathogen of humans that can cross the placenta and result in adverse pregnancy outcomes and long-term birth defects. The mechanisms used by T. gondii to cross the placenta are unknown, but complex interactions with the host immune response are likely to play a role in dictating infection outcomes during pregnancy. Prior work showed that T. gondii infection dramatically and specifically increases the secretion of the immunomodulatory chemokine CCL22 in human placental cells during infection. Given the important role of this chemokine during pregnancy, we hypothesized that CCL22 induction was driven by a specific T. gondii-secreted effector. Using a combination of bioinformatics and molecular genetics, we have now identified T. gondii GRA28 as the gene product required for CCL22 induction. GRA28 is secreted into the host cell, where it localizes to the nucleus, and deletion of the GRA28 gene results in reduced CCL22 placental cells as well as a human monocyte cell line. The impact of GRA28 on CCL22 production is also conserved in mouse immune and placental cells both in vitro and in vivo. Moreover, parasites lacking GRA28 are impaired in their ability to disseminate throughout the animal, suggesting a link between CCL22 induction and the ability of the parasite to cause disease. Overall, these data demonstrate a clear function for GRA28 in altering the immunomodulatory landscape during infection of both placental and peripheral immune cells and show a clear impact of this immunomodulation on infection outcome. IMPORTANCE Toxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in HIV/AIDS patients and can also cross the placenta and infect the developing fetus. We have found that placental and immune cells infected with T. gondii secrete significant amounts of a chemokine (called CCL22) that is critical for immune tolerance during pregnancy. In order to better understand whether this is a response by the host or a process that is driven by the parasite, we have identified a T. gondii gene that is absolutely required to induce CCL22 production in human cells, indicating that CCL22 production is a process driven almost entirely by the parasite rather than the host. Consistent with its role in immune tolerance, we also found that T. gondii parasites lacking this gene are less able to proliferate and disseminate throughout the host. Taken together, these data illustrate a direct relationship between CCL22 levels in the infected host and a key parasite effector and provide an interesting example of how T. gondii can directly modulate host signaling pathways in order to facilitate its growth and dissemination.


Assuntos
Quimiocina CCL22/metabolismo , Placenta/parasitologia , Complicações Parasitárias na Gravidez/metabolismo , Proteínas de Protozoários/metabolismo , Toxoplasma/metabolismo , Toxoplasmose/metabolismo , Animais , Quimiocina CCL22/genética , Feminino , Interações Hospedeiro-Parasita , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Placenta/metabolismo , Gravidez , Complicações Parasitárias na Gravidez/genética , Complicações Parasitárias na Gravidez/parasitologia , Proteínas de Protozoários/genética , Toxoplasma/genética , Toxoplasmose/genética , Toxoplasmose/parasitologia
12.
Mediators Inflamm ; 2021: 6652791, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557056

RESUMO

Thymus and Activation-Regulated Chemokine (TARC/CCL17) and Macrophage-Derived Chemokine (MDC/CCL22) are two key chemokines exerting their biological effect via binding and activating a common receptor CCR4, expressed at the surface of type 2 helper T (Th2) cells. By recruiting Th2 cells in the dermis, CCL17 and CCL22 promote the development of inflammation in atopic skin. The aim of this research was to develop a plant extract whose biological properties, when applied topically, could be beneficial for people with atopic-prone skin. The strategy which was followed consisted in identifying ligands able to neutralize the biological activity of CCL17 and CCL22. Thus, an in silico molecular modeling and a generic screening assay were developed to screen natural molecules binding and blocking these two chemokines. N-Feruloylserotonin was identified as a neutraligand of CCL22 in these experiments. A cornflower extract containing N-feruloylserotonin was selected for further in vitro tests: the gene expression modulation of inflammation biomarkers induced by CCL17 or CCL22 in the presence or absence of this extract was assessed in the HaCaT keratinocyte cell line. Additionally, the same cornflower extract in another vehicle was evaluated in parallel with N-feruloylserotonin for cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymatic cellular inhibition. The cornflower extract was shown to neutralize the two chemokines in vitro, inhibited COX-2 and 5-LOX, and demonstrated anti-inflammatory activities due mainly to the presence of N-feruloylserotonin. Although these findings would need to be confirmed in an in vivo study, the in vitro studies lay the foundation to explain the benefits of the cornflower extract when applied topically to individuals with atopic-prone skin.


Assuntos
Anti-Inflamatórios/farmacologia , Quimiocina CCL17/antagonistas & inibidores , Quimiocina CCL22/antagonistas & inibidores , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Lipoxigenase/farmacologia , Extratos Vegetais/farmacologia , Serotonina/análogos & derivados , Pele/efeitos dos fármacos , Zea mays/química , Células Cultivadas , Quimiocina CCL17/química , Quimiocina CCL22/química , Humanos , Simulação de Acoplamento Molecular , Extratos Vegetais/análise , Serotonina/química , Serotonina/farmacologia
13.
BMC Cancer ; 21(1): 922, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34391381

RESUMO

OBJECTIVE: Tongue and mouth floor squamous cell carcinoma (T/MF SCC) exhibits a high rate of local recurrence and cervical lymph node metastasis. The effect of the tumor microenvironment on T/MF SCC remains unclear. MATERIALS AND METHODS: Transcriptome and somatic mutation data of patients with T/MF SCC were obtained from HNSC projects of the Cancer Genome Atlas. Immune infiltration quantification in early- (clinical stage I-II) and advanced-stage (clinical stage III-IV) T/MF SCC was performed using single sample Gene Set Enrichment Analysis and MCPcounter. Differentially expressed gene data were filtered, and their function was assessed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Kaplan-Meier survival curve analysis and Cox regression model were conducted to evaluate the survival of patients with the CCL22 signature. Maftools was used to present the overview of somatic mutations. RESULTS: In T/MF SCC, T helper (Th)2 cell counts were significantly increased in patients with early-stage disease compared to those with advanced-stage disease. Expression of the Th2 cell-related chemokine, CCL22, was downregulated in patients with advanced-stage T/MF SCC. Univariate and multivariate Cox analyses revealed that CCL22 was a good prognostic factor in T/MF SCC. A nomogram based on the expression of CCL22 was constructed to serve as a prognostic indicator for T/MF SCC. NOTCH1 mutations were found at a higher rate in patients with advanced-stage T/MF SCC than in those with early-stage T/MF SCC, resulting in the inhibition of the activation of the NOTCH1-Th2 cell differentiation pathway. The expression levels of CCL22, GATA-3, and IL4 were higher in patients with early-stage T/MF SCC than in those with advanced-stage T/MF SCC. CONCLUSION: In T/MF SCC, high expression of CCL22 may promote the recruitment of Th2 cells and help predict a better survival. Mutations in NOTCH1 inhibit the differentiation of Th2 cells, facilitating tumor progression through a decrease in Th2 cell recruitment and differentiation.


Assuntos
Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Quimiocina CCL22/genética , Neoplasias Bucais/etiologia , Neoplasias Bucais/metabolismo , Receptor Notch1/genética , Células Th2/imunologia , Células Th2/metabolismo , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiotaxia de Leucócito/genética , Quimiotaxia de Leucócito/imunologia , Biologia Computacional/métodos , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Linfócitos do Interstício Tumoral , Masculino , Pessoa de Meia-Idade , Soalho Bucal/metabolismo , Soalho Bucal/patologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Mutação , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais
14.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208434

RESUMO

Skullcapflavone II (SFII), a flavonoid derived from Scutellaria baicalensis, has been reported to have anti-inflammatory properties. However, its therapeutic potential for skin inflammatory diseases and its mechanism are unknown. Therefore, this study aimed to investigate the effect of SFII on TNF-α/IFN-γ-induced atopic dermatitis (AD)-associated cytokines, such as thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC). Co-stimulation with TNF-α/IFN-γ in HaCaT cells is a well-established model for induction of pro-inflammatory cytokines. We treated cells with SFII prior to TNF-α/IFN-γ-stimulation and confirmed that it significantly inhibited TARC and MDC expression at the mRNA and protein levels. Additionally, SFII also inhibited the expression of cathepsin S (CTSS), which is associated with itching in patients with AD. Using specific inhibitors, we demonstrated that STAT1, NF-κB, and p38 MAPK mediate TNF-α/IFN-γ-induced TARC and MDC, as well as CTSS expression. Finally, we confirmed that SFII significantly suppressed TNF-α/IFN-γ-induced phosphorylation of STAT1, NF-κB, and p38 MAPK. Taken together, our study indicates that SFII inhibits TNF-α/IFN-γ-induced TARC, MDC, and CTSS expression by regulating STAT1, NF-κB, and p38 MAPK signaling pathways.


Assuntos
Catepsinas/biossíntese , Quimiocina CCL17/biossíntese , Quimiocina CCL22/biossíntese , Flavonoides/farmacologia , Interferon gama/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Catepsinas/genética , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL17/genética , Quimiocina CCL22/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células HaCaT , Humanos , Queratinócitos/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
PLoS Negl Trop Dis ; 15(6): e0009448, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34106920

RESUMO

BACKGROUND: In Mali, cutaneous leishmaniasis (CL) and filariasis are co-endemic. Previous studies in animal models of infection have shown that sand fly saliva enhance infectivity of Leishmania parasites in naïve hosts while saliva-specific adaptive immune responses may protect against cutaneous and visceral leishmaniasis. In contrast, the human immune response to Phlebotomus duboscqi (Pd) saliva, the principal sand fly vector in Mali, was found to be dichotomously polarized with some individuals having a Th1-dominated response and others having a Th2-biased response. We hypothesized that co-infection with filarial parasites may be an underlying factor that modulates the immune response to Pd saliva in endemic regions. METHODOLOGY/PRINCIPAL FINDINGS: To understand which cell types may be responsible for polarizing human responses to sand fly saliva, we investigated the effect of salivary glands (SG) of Pd on human monocytes. To this end, elutriated monocytes were cultured in vitro, alone, or with SG, microfilariae antigen (MF ag) of Brugia malayi, or LPS, a positive control. The mRNA expression of genes involved in inflammatory or regulatory responses was then measured as were cytokines and chemokines associated with these responses. Monocytes of individuals who were not exposed to sand fly bites (mainly North American controls) significantly upregulated the production of IL-6 and CCL4; cytokines that enhance leishmania parasite establishment, in response to SG from Pd or other vector species. This selective inflammatory response was lost in individuals that were exposed to sand fly bites which was not changed by co-infection with filarial parasites. Furthermore, infection with filarial parasites resulted in upregulation of CCL22, a type-2 associated chemokine, both at the mRNA levels and by its observed effect on the frequency of recruited monocytes. CONCLUSIONS/SIGNIFICANCE: Together, our data suggest that SG or recombinant salivary proteins from Pd alter human monocyte function by upregulating selective inflammatory cytokines.


Assuntos
Brugia Malayi/imunologia , Proteínas de Insetos/imunologia , Monócitos/parasitologia , Phlebotomus/imunologia , Saliva/imunologia , Imunidade Adaptativa , Animais , Células Cultivadas , Quimiocina CCL22/genética , Quimiocina CCL22/metabolismo , Coinfecção , Doenças Endêmicas , Filariose/complicações , Filariose/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Imunidade Celular , Leishmaniose Cutânea/complicações , Leishmaniose Cutânea/imunologia , Lipopolissacarídeos/toxicidade , Mali , Monócitos/fisiologia , RNA Mensageiro , Proteínas Recombinantes , Glândulas Salivares , Linfócitos T Auxiliares-Indutores
16.
Nature ; 592(7852): 133-137, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33597749

RESUMO

Antibody affinity maturation depends on positive selection in germinal centres (GCs) of rare B cell clones that acquire higher-affinity B cell receptors via somatic hypermutation, present more antigen to follicular helper T (TFH) cells and, consequently, receive more contact-dependent T cell help1. As these GC B cells and TFH cells do not maintain long-lasting contacts in the chaotic GC environment2-4, it is unclear how sufficient T cell help is cumulatively focused onto those rare clones. Here we show that, upon stimulation of CD40, GC B cells upregulate the chemokine CCL22 and to a lesser extent CCL17. By engaging the chemokine receptor CCR4 on TFH cells, CCL22 and CCL17 can attract multiple helper cells from a distance, thus increasing the chance of productive help. During a GC response, B cells that acquire higher antigen-binding affinities express higher levels of CCL22, which in turn 'highlight' these high-affinity GC B cells. Acute increase or blockade of TFH cells helps to rapidly increase or decrease CCL22 expression by GC B cells, respectively. Therefore, a chemokine-based intercellular reaction circuit links the amount of T cell help that individual B cells have received recently to their subsequent ability to attract more help. When CCL22 and CCL17 are ablated in B cells, GCs form but B cells are not affinity-matured efficiently. When competing with wild-type B cells in the same reaction, B cells lacking CCL22 and CCL17 receive less T cell help to maintain GC participation or develop into bone-marrow plasma cells. By uncovering a chemokine-mediated mechanism that highlights affinity-improved B cells for preferential help from TFH cells, our study reveals a principle of spatiotemporal orchestration of GC positive selection.


Assuntos
Quimiocina CCL22/metabolismo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Células Cultivadas , Quimiocina CCL17/deficiência , Quimiocina CCL17/genética , Quimiocina CCL22/deficiência , Quimiocina CCL22/genética , Feminino , Humanos , Masculino , Camundongos , Tonsila Palatina/citologia , Receptores CCR4/deficiência , Receptores CCR4/genética , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Regulação para Cima
17.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525403

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by an impaired skin barrier and intense itchiness, which decreases the individual's quality of life. No fully effective therapeutic agents have prevailed for AD due to an insufficient grasp of the complex etiology. Ellagic acid (EA), a natural compound, has anti-inflammatory properties in chronic diseases. The effects of EA on AD have not yet been explored. The present study investigated the effects of EA on TNF-α/IFN-γ-stimulated HaCaT keratinocytes and house dust mite-induced AD-like skin lesions in NC/Nga mice. Treatment with EA suppressed inflammatory responses in keratinocytes by regulating critical inflammatory signaling pathways, such as mitogen-activated protein kinases and signal transducers and activators of transcription. In vivo studies using a DfE-induced AD mouse model showed the effects of EA administration through ameliorated skin lesions via decremented histological inflammatory reactions. These results suggest that EA could be a potential therapeutic alternative for the treatment of AD by inhibiting inflammatory signaling pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Dermatite Atópica/tratamento farmacológico , Dermatophagoides farinae/química , Ácido Elágico/farmacologia , Proteínas Quinases Ativadas por Mitógeno/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Animais , Antígenos de Dermatophagoides/administração & dosagem , Quimiocina CCL17/genética , Quimiocina CCL17/imunologia , Quimiocina CCL22/genética , Quimiocina CCL22/imunologia , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Misturas Complexas/administração & dosagem , Citocinas/genética , Citocinas/imunologia , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatophagoides farinae/imunologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Células HaCaT , Humanos , Interferon gama/antagonistas & inibidores , Interferon gama/farmacologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/imunologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia
18.
J Leukoc Biol ; 109(2): 373-376, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32480426

RESUMO

Atypical chemokine receptors (ACKRs) have emerged as important regulators or scavengers of homeostatic and inflammatory chemokines. Among these atypical receptors, ACKR4 is reported to bind the homeostatic chemokines CCL19, CCL21, CCL25 and CXCL13. In a recent study by Matti et al., the authors show that ACKR4 is also a receptor for CCL20, previously established to bind to CCR6 only. They provide convincing evidence that, just as for its other chemokine ligands, ACKR4 rapidly internalizes CCL20 both in vitro and in vivo. Independently of this discovery, we undertook a screening program aiming at reassessing the activity of the 43 human chemokines toward ACKR4 using a highly sensitive ß-arrestin recruitment assay. This systematic analysis confirmed CCL20 as a new agonist ligand for ACKR4 in addition to CCL19, CCL21, and CCL25. Furthermore, CCL22, which plays an important role in both homeostasis and inflammatory responses, and is known as a ligand for CCR4 and ACKR2 was found to also act as a potent partial agonist of ACKR4. In contrast, agonist activity of CXCL13 toward ACKR4 was disproved. This independent wide-range systematic study confirms the pairing of CCL20 with ACKR4 newly discovered by Matti and co-authors, and further refines the spectrum of chemokines activating ACKR4.


Assuntos
Quimiocina CCL20/metabolismo , Quimiocina CCL22/metabolismo , Quimiocina CXCL13/metabolismo , Receptores CCR/agonistas , Receptores CCR/metabolismo , Sequência de Aminoácidos , Quimiocina CCL22/química , Humanos , Ligantes , Filogenia , Ligação Proteica , beta-Arrestinas/metabolismo
19.
Am J Respir Cell Mol Biol ; 64(3): 344-356, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33264064

RESUMO

The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then used to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface-differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-κB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.


Assuntos
Asma/patologia , Asma/virologia , Quimiocina CCL17/metabolismo , Quimiocina CCL22/metabolismo , Progressão da Doença , Rhinovirus/fisiologia , Fator de Transcrição STAT6/metabolismo , Células A549 , Adolescente , Adulto , Animais , Biomarcadores/metabolismo , Quimiocinas/metabolismo , Células Epiteliais/metabolismo , Feminino , Humanos , Cinética , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Doadores de Tecidos , Adulto Jovem
20.
Arq Gastroenterol ; 57(4): 366-374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33331471

RESUMO

BACKGROUND: During the Helicobacter pylori (HP) infection, the infiltration of the leukocytes into stomach mucosa is directed by locally produced chemokines that play a decisive role in infection outcome. The CagA is the most potent virulence factor of HP, so that the infection with CagA + strains is associated with more severe complications than infection with CagA - HP. OBJECTIVE: The aim was to determine the expression of chemokines CXCL10, CCL17, CCL20 and CCL22, and their receptors by CagA + HP- and CagA - HP-derived crude extract (HP-CE)-stimulated peripheral blood mononuclear cells (PBMCs) from peptic ulcer (PU) patients. METHODS: The serum and the PBMCs were collected from 20 HP-infected PU patients, 20 HP-infected asymptomatic subjects (HIA) and 20 non-infected healthy subjects (NHS). The PBMCs were cultured in absence of stimulator or with 10 µg CagA + HP crude extract (CagA + CE), 10 µg CagA - HP crude extract (CagA - CE). Chemokines and receptors were measured by ELISA and real time-PCR respectively. RESULTS: In PU patients, the production of chemokines CXCL10, CCL17, CCL20 and CCL22, and the expression of chemokine receptors CXCR3, CCR4 and CCR6 by CagA + CE-induced PBMCs were significantly higher than non-stimulated and CagA - CE stimulated cultures. The CXCL10 production by CagA + CE stimulated PBMCs from HIA subjects was significantly higher than the equal cultures from PU and NHS groups. The CCL17 and the CCL20 production by non-stimulated, CagA + CE stimulated, and CagA - CE stimulated PBMCs from PU subjects were significantly higher than the equal cultures from NHS and HIA groups. The CCL22 production by non-stimulated, CagA + CE stimulated and CagA - CE stimulated PBMCs from NHS group were significantly higher than the equal cultures from HIA and PU groups. The CagA + CE stimulated PBMCs from HIA subjects expressed lower amounts of CCR6 in comparison with CagA + CE stimulated PBMCs from NHS and PU groups. The serum levels CXCL10 and CCL20 in PU and HIA groups were significantly higher than NHS subjects. NHS and HIA groups displayed higher serum levels of CCL22 in comparison with PU patients. CONCLUSION: Results indicated that the CagA status of bacterium influence the expression of chemokines and receptors by HP-CE stimulated PBMCs from PU patients.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Úlcera Péptica , Antígenos de Bactérias , Proteínas de Bactérias , Quimiocina CCL17 , Quimiocina CCL20 , Quimiocina CCL22 , Quimiocina CXCL10 , Humanos , Leucócitos , Leucócitos Mononucleares , Fatores de Virulência
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