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1.
Theranostics ; 11(16): 7735-7754, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335961

RESUMO

Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death. The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC). In the "vicious cycle" of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC. Disrupting these cancer-stroma interactions would enhance treatment response. Methods: To disrupt this cycle, we orthogonally targeted nanomicelles (NM) loaded with non-therapeutic doses of a photosensitizer, titanocene (TC), to VLA-4 (α4ß1, CD49d/CD29) expressing MMC (MM1.S) and αvß3 (CD51/CD61) expressing OC. Concurrently, a non-lethal dose of a radiopharmaceutical, 18F-fluorodeoxyglucose ([18F]FDG) administered systemically interacted with TC (radionuclide stimulated therapy, RaST) to generate cytotoxic reactive oxygen species (ROS). The in vitro and in vivo effects of RaST were characterized in MM1.S cell line, as well as in xenograft and isograft MM animal models. Results: Our data revealed that RaST induced non-enzymatic hydroperoxidation of cellular lipids culminating in mitochondrial dysfunction, DNA fragmentation, and caspase-dependent apoptosis of MMC using VLA-4 avid TC-NMs. RaST upregulated the expression of BAX, Bcl-2, and p53, highlighting the induction of apoptosis via the BAK-independent pathway. The enhancement of multicopper oxidase enzyme F5 expression, which inhibits lipid hydroperoxidation and Fenton reaction, was not sufficient to overcome RaST-induced increase in the accumulation of irreversible function-perturbing α,ß-aldehydes that exerted significant and long-lasting damage to both DNA and proteins. In vivo, either VLA-4-TC-NM or αvß3-TC-NMs RaST induced a significant therapeutic effect on immunocompromised but not immunocompetent MM-bearing mouse models. Combined treatment with both VLA-4-TC-NM and αvß3-TC-NMs synergistically inhibited osteolysis, reduced tumor burden, and prevented rapid relapse in both in vivo models of MM. Conclusions: By targeting MM and bone cells simultaneously, combination RaST suppressed MM disease progression through a multi-prong action on the vicious cycle of bone cancer. Instead of using the standard multidrug approach, our work reveals a unique photophysical treatment paradigm that uses nontoxic doses of a single light-sensitive drug directed orthogonally to cancer and bone cells, followed by radionuclide-stimulated generation of ROS to inhibit tumor progression and minimize osteolysis in both immunocompetent murine and immunocompromised human MM models.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Compostos Organometálicos/farmacologia , Osteoclastos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Medula Óssea/metabolismo , Neoplasias Ósseas , Osso e Ossos/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fluordesoxiglucose F18/farmacologia , Humanos , Cadeias alfa de Integrinas/efeitos dos fármacos , Cadeias alfa de Integrinas/metabolismo , Camundongos , Mieloma Múltiplo/metabolismo , Compostos Organometálicos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteólise/patologia , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Nanomedicina Teranóstica/métodos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Am J Respir Crit Care Med ; 204(7): 826-841, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256007

RESUMO

Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T cells recognizing peptides derived from conserved viral proteins could enhance vaccine-induced cross-strain protection. Objectives: To investigate the kinetics, phenotypes, and function of influenza virus-specific CD8+ resident memory T (Trm) cells in the lower airway and infer the molecular pathways associated with their response to infection in vivo. Methods: Healthy volunteers, aged 18-55, were inoculated intranasally with influenza A/California/4/09(H1N1). Blood, upper airway, and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed by using self-reported diaries, and the nasal viral load was assessed by using quantitative PCR. T-cell responses were analyzed by using a three-color FluoroSpot assay, flow cytometry with MHC I-peptide tetramers, and RNA sequencing, with candidate markers being confirmed by using the immunohistochemistry results for endobronchial biopsy specimens. Measurements and Main Results: After challenge, 57% of participants became infected. Preexisting influenza-specific CD8+ T cells in blood correlated strongly with a reduced viral load, which peaked at Day 3. Influenza-specific CD8+ T cells in BAL fluid were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between preinfection CD8+ T cells in BAL fluid and blood by using RNA sequencing revealed 3,928 differentially expressed genes, including all major Trm-cell markers. However, gene set enrichment analysis of BAL-fluid CD8+ T cells showed primarily innate cell-related pathways and, during infection, included upregulation of innate chemokines (Cxcl1, Cxcl10, and Cxcl16) that were also expressed by CD8+ cells in bronchial tissues. Conclusions: CD8+ Trm cells in the human lung display innate-like gene and protein expression that demonstrates blurred divisions between innate and adaptive immunity. Clinical study registered with www.clinicaltrials.gov (NCT02755948).


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Inata/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Imunidade Adaptativa/genética , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/virologia , Linfócitos T CD8-Positivos/metabolismo , Quimiocinas/metabolismo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Influenza Humana/genética , Influenza Humana/virologia , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Cinética , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Carga Viral , Adulto Jovem
3.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34067987

RESUMO

Intraepithelial lymphocytes (IEL) are widely distributed within the small intestinal epithelial cell (IEC) layer and represent one of the largest T cell pools of the body. While implicated in the pathogenesis of intestinal inflammation, detailed insight especially into the cellular cross-talk between IELs and IECs is largely missing in part due to lacking methodologies to monitor this interaction. To overcome this shortcoming, we employed and validated a murine IEL-IEC (organoids) ex vivo co-culture model system. Using livecell imaging we established a protocol to visualize and quantify the spatio-temporal migratory behavior of IELs within organoids over time. Applying this methodology, we found that IELs lacking CD103 (i.e., integrin alpha E, ITGAE) surface expression usually functioning as a retention receptor for IELs through binding to E-cadherin (CD324) expressing IECs displayed aberrant mobility and migration patterns. Specifically, CD103 deficiency affected the ability of IELs to migrate and reduced their speed during crawling within organoids. In summary, we report a new technology to monitor and quantitatively assess especially migratory characteristics of IELs communicating with IEC ex vivo. This approach is hence readily applicable to study the effects of targeted therapeutic interventions on IEL-IEC cross-talk.


Assuntos
Antígenos CD/metabolismo , Movimento Celular , Processamento de Imagem Assistida por Computador/métodos , Cadeias alfa de Integrinas/metabolismo , Mucosa Intestinal/metabolismo , Linfócitos Intraepiteliais/metabolismo , Organoides/metabolismo , Linfócitos T/fisiologia , Animais , Técnicas de Cocultura , Imunofluorescência , Mucosa Intestinal/citologia , Linfócitos Intraepiteliais/citologia , Camundongos , Organoides/citologia , Análise Espaço-Temporal
4.
Cancer Sci ; 112(9): 3469-3483, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34157192

RESUMO

Renal carcinoma shows a high risk of invasion and metastasis without effective treatment. Herein, we developed a chitosan (CS) nanoparticle-mediated DNA vaccine containing an activated factor L-Myc and a tumor-specific antigen CAIX for renal carcinoma treatment. The subcutaneous tumor models were intramuscularly immunized with CS-pL-Myc/pCAIX or control vaccine, respectively. Compared with single immunization group, the tumor growth was significantly suppressed in CS-pL-Myc/pCAIX co-immunization group. The increased proportion and mature of CD11c+ DCs, CD8+ CD11c+ DCs and CD103+ CD11c+ DCs were observed in the splenocytes from CS-pL-Myc/pCAIX co-immunized mice. Furthermore, the enhanced antigen-specific CD8+ T lymphocyte proliferation, cytotoxic T lymphocyte (CTL) responses, and multi-functional CD8+ T cell induction were detected in CS-pL-Myc/pCAIX co-immunization group compared with CS-pCAIX immunization group. Of note, the depletion of CD8 T cells resulted in the reduction of CD8+ T cells or CD8+ CD11c+ DCs and the loss of anti-tumor efficacy induced by CS-pL-Myc/pCAIX vaccine, suggesting the therapeutic efficacy of the vaccine was required for CD8+ DCs and CD103+ DCs mediated CD8+ T cells responses. Likewise, CS-pL-Myc/pCAIX co-immunization also significantly inhibited the lung metastasis of renal carcinoma models accompanied with the increased induction of multi-functional CD8+ T cell responses. Therefore, these results indicated that CS-pL-Myc/pCAIX vaccine could effectively induce CD8+ DCs and CD103+ DCs mediated tumor-specific multi-functional CD8+ T cell responses and exert the anti-tumor efficacy. This vaccine strategy offers a potential and promising approach for solid or metastatic tumor treatment.


Assuntos
Antígenos CD/metabolismo , Antígenos de Neoplasias/administração & dosagem , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Anidrase Carbônica IX/administração & dosagem , Carcinoma de Células Renais/terapia , Quitosana/química , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos/métodos , Imunidade , Imunização/métodos , Cadeias alfa de Integrinas/metabolismo , Neoplasias Renais/terapia , Nanopartículas/química , Proteínas Proto-Oncogênicas c-myc/administração & dosagem , Vacinas de DNA/administração & dosagem , Animais , Antígenos de Neoplasias/genética , Anidrase Carbônica IX/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-myc/genética , Resultado do Tratamento , Vacinas de DNA/imunologia
5.
Cell Mol Life Sci ; 78(15): 5789-5805, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34129058

RESUMO

Integrin CD103 mediates the adhesion and tissue retention of T cells by binding to E-cadherin which is abundant on epithelial cells. Notably, CD103 is highly expressed on CD8 T cells but conspicuously absent on most CD4 T cells. The mechanism controlling such lineage-specific expression of CD103 remains unclear. Using a series of genetically engineered mouse models, here, we demonstrate that the regulatory mechanism of CD103 expression is distinct between CD4 and CD8 T cells, and that the transcription factor Runx3 plays an important but not an essential role in this process. We further found that the availability of integrin ß7 which heterodimerizes with CD103 was necessary but also constrained the surface expression of CD103. Notably, the forced surface expression of CD103 did not significantly alter the thymic development of conventional T cells but severely impaired the generation of MHC-II-restricted TCR transgenic T cells, revealing previously unappreciated aspects of CD103 in the selection and maturation of CD4 T cells. Unlike its effect on CD4 T cell development, however, CD103 overexpression did not significantly affect CD4 T cells in peripheral tissues. Moreover, the frequency and number of CD4 T cells in the small intestine epithelium did not increase even though E-cadherin is highly expressed in this tissue. Collectively, these results suggest that most mature CD4 T cells are refractory to the effects of CD103 expression, and that they presumably utilize CD103-independent pathways to control their tissue retention and residency.


Assuntos
Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Cadeias alfa de Integrinas/metabolismo , Animais , Caderinas/metabolismo , Feminino , Cadeias beta de Integrinas/metabolismo , Mucosa Intestinal/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
6.
J Cell Biol ; 220(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34047771

RESUMO

Mesenchymal-to-epithelial transition (MET) converts cells from migratory mesenchymal to polarized epithelial states. Despite its importance for both normal and pathological processes, very little is known about the regulation of MET in vivo. Here we exploit midgut morphogenesis in Drosophila melanogaster to investigate the mechanisms underlying MET. We show that down-regulation of the EMT transcription factor Serpent is required for MET, but not sufficient, as interactions with the surrounding mesoderm are also essential. We find that midgut MET relies on the secretion of specific laminins via the CopII secretory pathway from both mesoderm and midgut cells. We show that secretion of the laminin trimer containing the Wingblister α-subunit from the mesoderm is an upstream cue for midgut MET, leading to basal polarization of αPS1 integrin in midgut cells. Polarized αPS1 is required for the formation of a monolayered columnar epithelium and for the apical polarization of αPS3, Baz, and E-Cad. Secretion of a distinct LamininA-containing trimer from midgut cells is required to reinforce the localization of αPS1 basally, and αPS3 apically, for robust repolarization. Our data suggest that targeting these MET pathways, in conjunction with therapies preventing EMT, may present a two-pronged strategy toward blocking metastasis in cancer.


Assuntos
Sistema Digestório/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Laminina/metabolismo , Animais , Animais Geneticamente Modificados , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/genética , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Caderinas/genética , Caderinas/metabolismo , Movimento Celular , Polaridade Celular , Sistema Digestório/embriologia , Proteínas de Drosophila/genética , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Fatores de Transcrição GATA/genética , Fatores de Transcrição GATA/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Laminina/genética , Microscopia Confocal , Microscopia de Fluorescência , Transdução de Sinais , Fatores de Tempo , Imagem com Lapso de Tempo
7.
Life Sci ; 278: 119564, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961857

RESUMO

AIMS: Elevated intraocular pressure is primarily induced by the increased resistance of conventional outflow of aqueous humor. Dysfunction of the juxtacanalicular region of trabecular meshwork (TM) and Schlemm's canal (SC) endothelium, as the main conventional outflow tissue, have been implicated as the major reasons for the increased resistance. Integrins are widespread in these tissues, especially alpha8 integrin (ITGA8). We aim to investigate the properties of cells expressing ITGA8 in the conventional outflow tissue. MAIN METHODS: Fluorescence in situ hybridization (FISH) and immunofluorescence (IF) were performed to detect the mRNA and protein levels of ITGA8 in human conventional outflow tissue. ITGA8-positive cells were isolated from the cultured human TM cells through a magnetic bead-based approach. Flow Cytometry was used to determine the purification efficiency. The expressions of TM and SC biomarkers and dexamethasone-induced myocilin secretion capacity of ITGA8-positive cells was assessed by Real-time PCR, IF and Western blot. A gel contraction assay was performed to evaluate contractility of ITGA8-positive cells after endothelin 1 treatment. KEY FINDINGS: ITGA8 was found with robust expression near the inner wall of SC endothelium. After purification, the proportion of ITGA8-positive cells were increased by about 10%. ITGA8-positive cells were identified with the properties as SC endothelial cells, such as more robust expressions of SC biomarkers, less dexamethasone-inducible myocilin expression, and stronger contractility. SIGNIFICANCE: This study demonstrated that cells expressing ITGA8 in SC region possess more properties as SC endothelial cells. Our data implicate a crucial role of ITGA8 in aqueous humor (AH) outflow resistance regulation.


Assuntos
Humor Aquoso/metabolismo , Células Endoteliais/metabolismo , Glaucoma/metabolismo , Cadeias alfa de Integrinas/metabolismo , Pressão Intraocular , Malha Trabecular/metabolismo , Biomarcadores/metabolismo , Sobrevivência Celular , Proteínas do Citoesqueleto/metabolismo , Dexametasona/farmacologia , Endotelina-1/metabolismo , Endotélio/metabolismo , Proteínas do Olho/metabolismo , Glaucoma/fisiopatologia , Glucocorticoides/metabolismo , Glicoproteínas/metabolismo , Humanos , Hibridização in Situ Fluorescente , Integrinas/metabolismo
8.
Cells ; 10(3)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809734

RESUMO

With the increased awareness about the importance of the composition, organization, and stiffness of the extracellular matrix (ECM) for tissue homeostasis, there is a renewed need to understand the details of how cells recognize, assemble and remodel the ECM during dynamic tissue reorganization events. Fibronectin (FN) and fibrillar collagens are major proteins in the ECM of interstitial matrices. Whereas FN is abundant in cell culture studies, it is often only transiently expressed in the acute phase of wound healing and tissue regeneration, by contrast fibrillar collagens form a persistent robust scaffold in healing and regenerating tissues. Historically fibrillar collagens in interstitial matrices were seen merely as structural building blocks. Cell anchorage to the collagen matrix was thought to be indirect and occurring via proteins like FN and cell surface-mediated collagen fibrillogenesis was believed to require a FN matrix. The isolation of four collagen-binding integrins have challenged this dogma, and we now know that cells anchor directly to monomeric forms of fibrillar collagens via the α1ß1, α2ß1, α10ß1 and α11ß1 integrins. The binding of these integrins to the mature fibrous collagen matrices is more controversial and depends on availability of integrin-binding sites. With increased awareness about the importance of characterizing the total integrin repertoire on cells, including the integrin collagen receptors, the idea of an absolute dependence on FN for cell-mediated collagen fibrillogenesis needs to be re-evaluated. We will summarize data suggesting that collagen-binding integrins in vitro and in vivo are perfectly well suited for nucleating and supporting collagen fibrillogenesis, independent of FN.


Assuntos
Adesão Celular , Membrana Celular/metabolismo , Junções Célula-Matriz/metabolismo , Matriz Extracelular/metabolismo , Colágenos Fibrilares/metabolismo , Cadeias alfa de Integrinas/metabolismo , Cadeias beta de Integrinas/metabolismo , Animais , Sítios de Ligação , Fibronectinas/metabolismo , Humanos , Ligação Proteica , Multimerização Proteica
9.
Diabetes ; 70(4): 955-965, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33531355

RESUMO

The NOD mouse develops spontaneous type 1 diabetes, with some features of disease that are very similar to the human disease. However, a proportion of NOD mice are naturally protected from developing diabetes, and currently, studies characterizing this cohort are very limited. Here, using both immunofluorescence and multiparameter flow cytometry, we focus on the pancreatic islet morphology and immune infiltrate observed in naturally protected NOD mice. We show that naturally protected NOD mice are characterized by an increased frequency of insulin-containing, smaller-sized, pancreatic islets. Although mice remain diabetes free, florid immune infiltrate remains. However, this immune infiltrate is skewed toward a regulatory phenotype in both T- and B-cell compartments. Pancreatic islets have an increased frequency of IL-10-producing B cells and associated cell surface markers. Resident memory CD69+CD8+ T cells show a significant shift toward reduced CD103 expression, while CD4+ T cells have increased FoxP3+CTLA4+ expression. These data indicate that naturally protected NOD mice have a unique islet signature and provide new insight into regulatory mechanisms within pancreatic islets.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Ilhotas Pancreáticas/metabolismo , Animais , Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Diabetes Mellitus Tipo 1/genética , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Cadeias alfa de Integrinas/metabolismo , Camundongos
10.
J Leukoc Biol ; 109(5): 877-890, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33438263

RESUMO

Neutrophil-macrophage interplay is a fine-tuning mechanism that regulates the innate immune response during infection and inflammation. Cell surface receptors play an essential role in neutrophil and macrophage functions. The same receptor can provide different outcomes within diverse leukocyte subsets in different inflammatory conditions. Understanding the variety of responses mediated by one receptor is critical for the development of anti-inflammatory treatments. In this study, we evaluated the role of a leukocyte adhesive receptor, integrin αD ß2 , in the development of acute inflammation. αD ß2 is mostly expressed on macrophages and contributes to the development of chronic inflammation. In contrast, we found that αD -knockout dramatically increases mortality in the cecal ligation and puncture sepsis model and LPS-induced endotoxemia. This pathologic outcome of αD -deficient mice is associated with a reduced number of monocyte-derived macrophages and an increased number of neutrophils in their lungs. However, the tracking of adoptively transferred fluorescently labeled wild-type (WT) and αD -/- monocytes in WT mice during endotoxemia demonstrated only a moderate difference between the recruitment of these two subsets. Moreover, the rescue experiment, using i.v. injection of WT monocytes to αD -deficient mice followed by LPS challenge, showed only slightly reduced mortality. Surprisingly, the injection of WT neutrophils to the bloodstream of αD -/- mice markedly increased migration of monocyte-derived macrophage to lungs and dramatically improves survival. αD -deficient neutrophils demonstrate increased necrosis/pyroptosis. αD ß2 -mediated macrophage accumulation in the lungs promotes efferocytosis that reduced mortality. Hence, integrin αD ß2 implements a complex defense mechanism during endotoxemia, which is mediated by macrophages via a neutrophil-dependent pathway.


Assuntos
Endotoxemia/imunologia , Cadeias alfa de Integrinas/metabolismo , Neutrófilos/metabolismo , Sepse/imunologia , Transferência Adotiva , Animais , Ceco/patologia , Contagem de Células , Movimento Celular , Citocinas/sangue , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/complicações , Cadeias alfa de Integrinas/deficiência , Ligadura , Lipopolissacarídeos , Pulmão/patologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Monócitos/patologia , Necrose , Neutrófilos/patologia , Fagocitose , Punções , Piroptose , Sepse/sangue , Sepse/complicações , Análise de Sobrevida , Regulação para Cima
11.
Am J Physiol Gastrointest Liver Physiol ; 320(4): G420-G438, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33470153

RESUMO

Intestinal epithelia are critical for maintaining gastrointestinal homeostasis. Epithelial barrier injury, causing inflammation and vascular damage, results in inflammatory hypoxia, and thus, healing occurs in an oxygen-restricted environment. The transcription factor hypoxia-inducible factor (HIF)-1 regulates genes important for cell survival and repair, including the cell adhesion protein ß1-integrin. Integrins function as αß-dimers, and α-integrin-matrix binding is critical for cell migration. We hypothesized that HIF-1 stabilization accelerates epithelial migration through integrin-dependent pathways. We aimed to examine functional and posttranslational activity of α-integrins during HIF-1-mediated intestinal epithelial healing. Wound healing was assessed in T84 monolayers over 24 h with/without prolyl-hydroxylase inhibitor (PHDi) (GB-004), which stabilizes HIF-1. Gene and protein expression were measured by RT-PCR and immunoblot, and α-integrin localization was assessed by immunofluorescence. α-integrin function was assessed by antibody-mediated blockade, and integrin α6 regulation was determined by HIF-1α chromatin immunoprecipitation. Models of mucosal wounding and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis were used to examine integrin expression and localization in vivo. PHDi treatment accelerated wound closure and migration within 12 h, associated with increased integrin α2 and α6 protein, but not α3. Functional blockade of integrins α2 and α6 inhibited PHDi-mediated accelerated wound closure. HIF-1 bound directly to the integrin α6 promoter. PHDi treatment accelerated mucosal healing, which was associated with increased α6 immunohistochemical staining in wound-associated epithelium and wound-adjacent tissue. PHDi treatment increased α6 protein levels in colonocytes of TNBS mice and induced α6 staining in regenerating crypts and reepithelialized inflammatory lesions. Together, these data demonstrate a role for HIF-1 in regulating both integrin α2 and α6 responses during intestinal epithelial healing.NEW & NOTEWORTHY HIF-1 plays an important role in epithelial restitution, selectively inducing integrins α6 and α2 to promote migration and proliferation, respectively. HIF-stabilizing prolyl-hydroxylase inhibitors accelerate intestinal mucosal healing by inducing epithelial integrin expression.


Assuntos
Colite/prevenção & controle , Colo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Cadeias alfa de Integrinas/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Inibidores de Prolil-Hidrolase/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Cadeias alfa de Integrinas/genética , Integrina alfa2/metabolismo , Integrina alfa6/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos Endogâmicos BALB C , Estabilidade Proteica , Transdução de Sinais , Ácido Trinitrobenzenossulfônico
12.
Eur J Immunol ; 51(1): 151-166, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32762051

RESUMO

Tissue-resident memory CD8+ T cells (TRM ) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (TCM ) and effector memory CD8+ T cells (TEM ) also contribute to tissue recall responses, but their potential to form mucosal TRM remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of TCM and TEM at mucosal sites. Donor TCM and TEM exhibited robust systemic recall responses, but only limited accumulation in the small intestine, consistent with reduced expression of tissue-homing and -retention molecules. Murine and human circulating memory T cells also exhibited limited CD103 upregulation following TGF-ß stimulation. Upon pathogen clearance, TCM and TEM readily gave rise to secondary TEM . TCM also formed secondary central memory in lymphoid tissues and TRM in internal tissues, for example, the liver. Both TCM and TEM failed to substantially contribute to resident mucosal memory in the small intestine, while activated intestinal TRM , but not liver TRM , efficiently reformed CD103+ TRM . Our findings demonstrate that circulating TCM and TEM are limited in generating mucosal TRM upon reinfection. This may pose important implications on cell therapy and vaccination strategies employing memory CD8+ T cells for protection at mucosal sites.


Assuntos
Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas , Memória Imunológica , Cadeias alfa de Integrinas/imunologia , Imunidade Adaptativa , Transferência Adotiva , Animais , Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Feminino , Humanos , Cadeias alfa de Integrinas/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Intestino Delgado/citologia , Intestino Delgado/imunologia , Ativação Linfocitária , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/citologia , Membrana Mucosa/imunologia , Fator de Crescimento Transformador beta/imunologia
13.
Am J Physiol Lung Cell Mol Physiol ; 320(2): L193-L204, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33112186

RESUMO

Premature infants, especially those with bronchopulmonary dysplasia (BPD), develop recurrent severe respiratory viral illnesses. We have shown that hyperoxic exposure of immature mice, a model of BPD, increases lung IL-12-producing Clec9a+ CD103+ dendritic cells (DCs), pro-inflammatory responses, and airway hyperreactivity following rhinovirus (RV) infection. However, the requirement for CD103+ DCs and Clec9a, a DAMP receptor that binds necrotic cell cytoskeletal filamentous actin (F-actin), for RV-induced inflammatory responses has not been demonstrated. To test this, 2-day-old C57BL/6J, CD103+ DC-deficient Batf3-/- or Clec9agfp-/- mice were exposed to normoxia or hyperoxia for 14 days. Also, selected mice were treated with neutralizing antibody against CD103. Immediately after hyperoxia, the mice were inoculated with RV intranasally. We found that compared with wild-type mice, hyperoxia-exposed Batf3-/- mice showed reduced levels of IL-12p40, IFN-γ, and TNF-α, fewer IFN-γ-producing CD4+ T cells, and decreased airway responsiveness following RV infection. Similar effects were observed in anti-CD103-treated and Clec9agfp-/- mice. Furthermore, hyperoxia increased airway dead cell number and extracellular F-actin levels. Finally, studies in preterm infants with respiratory distress syndrome showed that tracheal aspirate CLEC9A expression positively correlated with IL12B expression, consistent with the notion that CLEC9A+ cells are responsible for IL-12 production in humans as well as mice. We conclude that CD103+ DCs and Clec9a are required for hyperoxia-induced pro-inflammatory responses to RV infection. In premature infants, Clec9a-mediated activation of CD103+ DCs may promote pro-inflammatory responses to viral infection, thereby driving respiratory morbidity.


Assuntos
Antígenos CD/metabolismo , Células Dendríticas/imunologia , Hiperóxia/fisiopatologia , Cadeias alfa de Integrinas/metabolismo , Lectinas Tipo C/fisiologia , Pulmão/imunologia , Pneumonia/imunologia , Receptores Imunológicos/fisiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/imunologia , Animais , Animais Recém-Nascidos , Antígenos CD/genética , Fatores de Transcrição de Zíper de Leucina Básica/fisiologia , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro/imunologia , Cadeias alfa de Integrinas/genética , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Picornaviridae/complicações , Infecções por Picornaviridae/virologia , Pneumonia/virologia , Proteínas Repressoras/fisiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/metabolismo , Síndrome do Desconforto Respiratório do Recém-Nascido/patologia , Rhinovirus/isolamento & purificação
14.
Methods Mol Biol ; 2217: 57-69, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33215377

RESUMO

Integrins are heterodimeric adhesion receptors that maintain cell-extracellular matrix (ECM) interactions in diverse tissue microenvironments. They mediate cell adhesion and signaling through the assembly of large cytoplasmic multiprotein complexes that focally connect with the cytoskeleton. Integrin adhesion complexes (IAC) are specialized by the type of integrin-ECM contact and are sensitive to mechanical forces. Thus, they encrypt context-dependent information about the microenvironment in their composition. Signals mediated through IACs modulate many aspects of cell behavior, which allows cells to adapt to their surroundings. To gain insights into their function, IACs have been isolated from cultured cells and explored by proteomics. IACs are insoluble by nature and held together by transient/weak interactions, which makes it challenging to isolate intact IACs. Usually all IACs coupled to a specified ECM, which may employ different integrins, are isolated. Here we describe an alternative method based on proximity-dependent biotin identification (BioID), where specific integrin interaction partners are labeled in live cells and isolated without the need to isolate intact IACs.


Assuntos
Bioensaio , Carbono-Nitrogênio Ligases/metabolismo , Proteínas de Escherichia coli/metabolismo , Cadeias alfa de Integrinas/metabolismo , Cadeias beta de Integrinas/metabolismo , Mapeamento de Interação de Proteínas/métodos , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/metabolismo , Sequência de Aminoácidos , Animais , Biotina/química , Biotina/metabolismo , Biotinilação , Carbono-Nitrogênio Ligases/genética , Adesão Celular , Membrana Celular/química , Membrana Celular/metabolismo , Cães , Proteínas de Escherichia coli/genética , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Cadeias alfa de Integrinas/classificação , Cadeias alfa de Integrinas/genética , Cadeias beta de Integrinas/classificação , Cadeias beta de Integrinas/genética , Células Madin Darby de Rim Canino , Plasmídeos/química , Plasmídeos/metabolismo , Ligação Proteica , Multimerização Proteica , Proteínas Recombinantes de Fusão/genética , Proteínas Repressoras/genética , Coloração e Rotulagem/métodos , Transfecção
15.
Methods Mol Biol ; 2217: 71-81, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33215378

RESUMO

The in situ proximity ligation assay (PLA) is capable of detecting single protein events such as protein protein-interactions and posttranslational modifications (e.g., protein phosphorylation) in tissue and cell samples prepared for analysis by immunofluorescent or immunohistochemical microscopy. The targets are detected using two primary antibodies which must be from different host species. A pair of secondary antibodies (PLA probes) conjugated to complementary oligonucleotides is applied to the sample, and a signal is generated only when the two PLA probes are in close proximity by their binding to the two primary antibodies that have bound to their targets in close proximity. The signal from each pair of PLA probes is visualized as an individual fluorescent spot. These PLA signals can be quantified (counted) using image analysis software (ImageJ), and also assigned to a specific subcellular location based on microscopy image overlays. In principle, in situ PLA offers a relatively simple and sensitive technique to analyze interactions among any proteins for which suitable antibodies are available. Integrin-mediated focal adhesions (FAs) are large multiprotein complexes consisting of more than 150 proteins, also known as the integrin adhesome, which link the extracellular matrix (ECM) to the actin cytoskeleton and regulate the functioning of mechanosignaling pathways. The in situ PLA approach is well suited for examining the spatiotemporal aspects of protein posttranslational modifications and protein interactions occurring in dynamic multiprotein complexes such as integrin mediated focal adhesions.


Assuntos
Adesões Focais/metabolismo , Imuno-Histoquímica/métodos , Cadeias alfa de Integrinas/metabolismo , Integrina beta1/metabolismo , Complexos Multiproteicos/metabolismo , Oligonucleotídeos/metabolismo , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Anticorpos/química , Matriz Extracelular/metabolismo , Matriz Extracelular/ultraestrutura , Adesões Focais/ultraestrutura , Mucosa Gástrica/metabolismo , Mucosa Gástrica/ultraestrutura , Humanos , Processamento de Imagem Assistida por Computador , Cadeias alfa de Integrinas/química , Integrina beta1/química , Microscopia de Fluorescência , Sondas Moleculares/química , Sondas Moleculares/metabolismo , Complexos Multiproteicos/química , Músculo Liso/metabolismo , Músculo Liso/ultraestrutura , Oligonucleotídeos/síntese química , Ligação Proteica
16.
Biochem Biophys Res Commun ; 534: 34-40, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310185

RESUMO

Abnormal crosstalk between gut immune and the liver was involved in nonalcoholic steatohepatitis (NASH). Mice with methionine choline-deficient (MCD) diet-induced NASH presented an imbalance of pro-(IL-6 and IFN-γ) and anti-inflammatory cytokines (IL-10) in the intestine. We also clarified that the ratio of CD4+ T cells and found that the NASH mesenteric lymph node (MLN) presents decreased numbers of CD4+Th17 cells but increased numbers of CD4+CD8+FoxP3+ regulatory T cells (Tregs). Furthermore, the intestinal immune imbalance in NASH was attributed to impaired gut chemokine receptor 9 (CCR9)/chemokine ligand 25 (CCL25) signalling, which is a crucial pathway for immune cell homing in the gut. We also demonstrated that CD4+CCR9+ T cell homing was dependent on CCL25 and that the numbers and migration abilities of CD4+CCR9+ T cells were reduced in NASH. Interestingly, the analysis of dendritic cell (DC) subsets showed that the numbers and retinal dehydrogenase (RALDH) activity of CD103+CD11b+ DCs were decreased and that the ability of these cells to upregulate CD4+ T cell CCR9 expression was damaged in NASH. Taken together, impaired intestinal CCR9/CCL25 signalling induced by CD103+CD11b+ DC dysfunction contributes to the gut immune imbalance observed in NASH.


Assuntos
Quimiocinas CC/metabolismo , Células Dendríticas/imunologia , Intestinos/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptores CCR/metabolismo , Alanina Transaminase/sangue , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Aspartato Aminotransferases/sangue , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Quimiocinas CC/genética , Deficiência de Colina/complicações , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Cadeias alfa de Integrinas/imunologia , Cadeias alfa de Integrinas/metabolismo , Intestinos/fisiopatologia , Masculino , Metionina/deficiência , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores CCR/genética , Transdução de Sinais
17.
Int J Mol Sci ; 21(23)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33287461

RESUMO

Background-Elevated circulating fatty-acid-binding protein 4 (FABP4) levels may be linked with cardiovascular events. This study aimed to investigate the mechanistic role of FABP4 in atherosclerosis. Methods-We recruited 22 patients with angiographically proven coronary artery disease (CAD) and 40 control subjects. Mononuclear cells (MNCs) and human coronary endothelial cells (HCAECs) were used for in vitro study. Results-Patients with CAD were predominantly male with an enhanced prevalence of hypertension, diabetes, and smoking history. FABP4 concentrations were up-regulated in culture supernatants of MNCs from CAD patients, which were positively correlated with the patients' age, waist-hip ratio, body mass index, serum creatinine, type 2 diabetes, and the presence of hypertension. The adhesiveness of HCAECs to monocytic cells can be activated by FABP4, which was reversed by an FABP4 antibody. FABP4 blockade attenuated the oxidized low-density lipoprotein (oxLDL)-induced expression of ICAM-1, VCAM-1, and P-selectin. FABP4 impaired the tube formation and migration via the ERK/JNK/STAT-1 signaling pathway. FABP4 suppressed phosphorylation of eNOS and expression of SDF-1 protein, both of which can be reversed by treatment with VEGF. Blockade of FABP4 also improved the oxLDL-impaired cell function. Conclusion-We discovered a novel pathogenic role of FABP4 in MNC activation and endothelial dysfunction in atherosclerosis. FABP4 may be a therapeutic target for modulating atherosclerosis.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Idoso , Aterosclerose/patologia , Antígenos CD18/metabolismo , Adesão Celular , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Suscetibilidade a Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Cadeias alfa de Integrinas/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
18.
J Virol ; 95(2)2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33115867

RESUMO

Latent HIV infection is the main barrier to cure, and most HIV-infected cells reside in the gut, where distinct but unknown mechanisms may promote viral latency. Transforming growth factor ß (TGF-ß), which induces the expression of CD103 on tissue-resident memory T cells, has been implicated in HIV latency. Using CD103 as a surrogate marker to identify cells that have undergone TGF-ß signaling, we compared the HIV RNA/DNA contents and cellular transcriptomes of CD103+ and CD103- CD4 T cells from the blood and rectum of HIV-negative (HIV-) and antiretroviral therapy (ART)-suppressed HIV-positive (HIV+) individuals. Like gut CD4+ T cells, circulating CD103+ cells harbored more HIV DNA than did CD103- cells but transcribed less HIV RNA per provirus. Circulating CD103+ cells also shared a gene expression profile that is closer to that of gut CD4 T cells than to that of circulating CD103- cells, with significantly lower expression levels of ribosomal proteins and transcriptional and translational pathways associated with HIV expression but higher expression levels of a subset of genes implicated in suppressing HIV transcription. These findings suggest that blood CD103+ CD4 T cells can serve as a model to study the molecular mechanisms of HIV latency in the gut and reveal new cellular factors that may contribute to HIV latency.IMPORTANCE The ability of HIV to establish a reversibly silent, "latent" infection is widely regarded as the main barrier to curing HIV. Most HIV-infected cells reside in tissues such as the gut, but it is unclear what mechanisms maintain HIV latency in the blood or gut. We found that circulating CD103+ CD4+ T cells are enriched for HIV-infected cells in a latent-like state. Using RNA sequencing (RNA-seq), we found that CD103+ T cells share a cellular transcriptome that more closely resembles that of CD4+ T cells from the gut, suggesting that they are homing to or from the gut. We also identified the cellular genes whose expression distinguishes gut CD4+ or circulating CD103+ T cells from circulating CD103- T cells, including some genes that have been implicated in HIV expression. These genes may contribute to latent HIV infection in the gut and may serve as new targets for therapies aimed at curing HIV.


Assuntos
Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/virologia , Trato Gastrointestinal/virologia , Infecções por HIV/virologia , HIV-1/fisiologia , Cadeias alfa de Integrinas/metabolismo , Transcrição Genética/genética , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , DNA Viral/metabolismo , Trato Gastrointestinal/imunologia , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Humanos , Linfócitos Intraepiteliais/metabolismo , Linfócitos Intraepiteliais/virologia , Provírus/fisiologia , RNA Viral/metabolismo , Proteínas Ribossômicas/genética , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/virologia , Latência Viral
19.
Hum Immunol ; 81(10-11): 634-643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32771274

RESUMO

The interaction of tolerogenic CD103+ dendritic cells (DCs) with regulatory T (Tregs) cells modulates immune responses by inducing immune tolerance. Hence, we determined the proportion of these cells in the peripheral blood mononuclear cells (PBMC) of asthmatic patients. We observed lower trends of CD11b-CD103+ DCs and CD86 within CD11b-CD103+ DCs, while increased levels of Foxp3 expressing CD25+/-TNFR2+ cells in asthmatics. There was a positive correlation in the expression of Foxp3 within CD3+CD4+CD25+TNFR2+ Tregs and CD11b-CD103+ as well as the expression of CD86 within HLA-DR+CD11c+CD11b-CD103+ DCs. In conclusion, we suggest that the increased levels of Tregs in blood could continuously suppress the T helper 2 (Th2) cells activation in the circulation which is also supported by the increase of anti-inflammatory cytokines IL-10 and TNF. Overall, functional immunoregulation of the regulatory cells, particularly Tregs, exhibit immune suppression and induce immune tolerance linked with the immune activation by the antigen presenting cells (APC).


Assuntos
Antígenos CD/metabolismo , Asma/sangue , Asma/imunologia , Células Dendríticas/imunologia , Cadeias alfa de Integrinas/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Tolerância Imunológica , Interleucina-10/sangue , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Células Th2/imunologia , Fatores de Necrose Tumoral/sangue , Adulto Jovem
20.
Immunology ; 161(3): 230-244, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32737889

RESUMO

Retinoic acid (RA) is an active derivative of vitamin A and a key regulator of immune cell function. In dendritic cells (DCs), RA drives the expression of CD103 (integrin αE ), a functionally relevant DC subset marker. In this study, we analyzed the cell type specificity and the molecular mechanisms involved in RA-induced CD103 expression. We show that RA treatment caused a significant up-regulation of CD103 in differentiated monocyte-derived DCs and blood DCs, but not in differentiated monocyte-derived macrophages or T cells. DC treatment with an RA receptor α (RARα) agonist led to an increase in CD103 expression similar to that in RA treatment, whereas RARA gene silencing with small interfering RNA blocked RA-induced up-regulation of CD103, pointing to a major role of RARα in the regulation of CD103 expression. To elucidate RA-induced signaling downstream of RARα, we used Western blot analysis of RA-treated DCs and showed a significant increase of p38 mitogen-activated protein kinase (MAPK) phosphorylation. In addition, DCs cultured with RA and a p38 MAPK inhibitor had a significantly reduced expression of CD103 compared with DCs cultured with RA only, indicating that p38 MAPK is involved in CD103 regulation. In summary, these findings suggest that the RA-induced expression of CD103 is specific to DCs, is mediated primarily through RARα and involves p38 MAPK signaling.


Assuntos
Antígenos CD/metabolismo , Células Dendríticas/imunologia , Cadeias alfa de Integrinas/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Tretinoína/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antígenos CD/genética , Diferenciação Celular , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Cadeias alfa de Integrinas/genética , Fosforilação , RNA Interferente Pequeno/genética , Receptor alfa de Ácido Retinoico/genética , Transdução de Sinais
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