Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.050
Filtrar
1.
PLoS Negl Trop Dis ; 15(7): e0009638, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34310619

RESUMO

BACKGROUND: The leishmaniases are a group of sandfly-transmitted diseases caused by species of the protozoan parasite, Leishmania. With an annual incidence of 1 million cases, 1 billion people living in Leishmania-endemic regions, and nearly 30,000 deaths each year, leishmaniasis is a major global public health concern. While phlebotomine sandflies are well-known as vectors of Leishmania, they are also the vectors of various phleboviruses, including Sandfly Fever Sicilian Virus (SFSV). Cutaneous leishmaniasis (CL), caused by Leishmania major (L. major), among other species, results in development of skin lesions on the infected host. Importantly, there exists much variation in the clinical manifestation between individuals. We propose that phleboviruses, vectored by and found in the same sandfly guts as Leishmania, may be a factor in determining CL severity. It was reported by our group that Leishmania exosomes are released into the gut of the sandfly vector and co-inoculated during blood meals, where they exacerbate CL skin lesions. We hypothesized that, when taking a blood meal, the sandfly vector infects the host with Leishmania parasites and exosomes as well as phleboviruses, and that this viral co-infection results in a modulation of leishmaniasis. METHODOLOGY/PRINCIPAL FINDINGS: In vitro, we observed modulation by SFSV in MAP kinase signaling as well as in the IRF3 pathway that resulted in a pro-inflammatory phenotype. Additionally, we found that SFSV and L. major co-infection resulted in an exacerbation of leishmaniasis in vivo, and by using endosomal (Toll-like receptor) TLR3, and MAVS knock-out mice, deduced that SFSV's hyperinflammatory effect was TLR3- and MAVS-dependent. Critically, we observed that L. major and SFSV co-infected C57BL/6 mice demonstrated significantly higher parasite burden than mice solely infected with L. major. Furthermore, viral presence increased leukocyte influx in vivo. This influx was accompanied by elevated total extracellular vesicle numbers. Interestingly, L. major displayed higher infectiveness with coincident phleboviral infection compared to L. major infection alone. CONCLUSION/SIGNIFICANCE: Overall our work represents novel findings that contribute towards understanding the causal mechanisms governing cutaneous leishmaniasis pathology. Better comprehension of the potential role of viral co-infection could lead to treatment regimens with enhanced effectiveness.


Assuntos
Infecções por Bunyaviridae/complicações , Leishmaniose Cutânea/complicações , Macrófagos/metabolismo , Células Mieloides/metabolismo , Phlebovirus , Animais , Linhagem Celular , Coinfecção , Feminino , Imunidade Inata , Inflamação , Fator Regulador 3 de Interferon , Leishmania major , Sistema de Sinalização das MAP Quinases , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/parasitologia , Células Mieloides/virologia , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismo
2.
J Vet Sci ; 22(3): e39, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34056880

RESUMO

BACKGROUND: Interferon lambda receptor 1 (IFNLR1) is a type II cytokine receptor that clings to interleukins IL-28A, IL29B, and IL-29 referred to as type III IFNs (IFN-λs). IFN-λs act through the JAK-STAT signaling pathway to exert antiviral effects related to preventing and curing an infection. Although the immune function of IFN-λs in virus invasion has been described, the molecular mechanism of IFNLR1 in that process is unclear. OBJECTIVES: The purpose of this study was to elucidate the role of IFNLR1 in the pathogenesis and treatment of porcine reproductive and respiratory syndrome virus (PRRSV). METHODS: The effects of IFNLR1 on the proliferation of porcine alveolar macrophages (PAMs) during PRRSV infection were investigated using interference and overexpression methods. RESULTS: In this study, the expressions of the IFNLR1 gene in the liver, large intestine, small intestine, kidney, and lung tissues of Dapulian pigs were significantly higher than those in Landrace pigs. It was determined that porcine IFNLR1 overexpression suppresses PRRSV replication. The qRT-PCR results revealed that overexpression of IFNLR1 upregulated antiviral and IFN-stimulated genes. IFNLR1 overexpression inhibits the proliferation of PAMs and upregulation of p-STAT1. By contrast, knockdown of IFNLR1 expression promotes PAMs proliferation. The G0/G1 phase proportion in IFNLR1-overexpressing cells increased, and the opposite change was observed in IFNLR1-underexpressing cells. After inhibition of the JAK/STAT signaling pathway, the G2/M phase proportion in the IFNLR1-overexpressing cells showed a significant increasing trend. In conclusion, overexpression of IFNLR1 induces activation of the JAK/STAT pathway, thereby inhibiting the proliferation of PAMs infected with PRRSV. CONCLUSION: Expression of the IFNLR1 gene has an important regulatory role in PRRSV-infected PAMs, indicating it has potential as a molecular target in developing a new strategy for the treatment of PRRSV.


Assuntos
Macrófagos Alveolares/virologia , Síndrome Respiratória e Reprodutiva Suína/fisiopatologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Receptores de Interferon/metabolismo , Animais , Linhagem Celular , Macrófagos Alveolares/metabolismo , Síndrome Respiratória e Reprodutiva Suína/virologia , Sus scrofa , Suínos
3.
Nat Commun ; 12(1): 2624, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976143

RESUMO

The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.


Assuntos
Colite Ulcerativa/imunologia , Interferons/metabolismo , Mucosa Intestinal/patologia , Reepitelização/imunologia , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Células Epiteliais , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Knockout , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Organismos Livres de Patógenos Específicos
4.
Nat Commun ; 12(1): 2620, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976173

RESUMO

Tumor associated macrophage responses are regulated by distinct metabolic states that affect their function. However, the ability of specific signals in the local tumor microenvironment to program macrophage metabolism remains under investigation. Here, we identify NAMPT, the rate limiting enzyme in NAD salvage synthesis, as a target of STAT1 during cellular activation by interferon gamma, an important driver of macrophage polarization and antitumor responses. We demonstrate that STAT1 occupies a conserved element within the first intron of Nampt, termed Nampt-Regulatory Element-1 (NRE1). Through disruption of NRE1 or pharmacological inhibition, a subset of M1 genes is sensitive to NAMPT activity through its impact on glycolytic processes. scRNAseq is used to profile in vivo responses by NRE1-deficient, tumor-associated leukocytes in melanoma tumors through the creation of a unique mouse strain. Reduced Nampt and inflammatory gene expression are present in specific myeloid and APC populations; moreover, targeted ablation of NRE1 in macrophage lineages results in greater tumor burden. Finally, elevated NAMPT expression correlates with IFNγ responses and melanoma patient survival. This study identifies IFN and STAT1-inducible Nampt as an important factor that shapes the metabolic program and function of tumor associated macrophages.


Assuntos
Citocinas/genética , Melanoma/genética , Nicotinamida Fosforribosiltransferase/genética , Fator de Transcrição STAT1/metabolismo , Neoplasias Cutâneas/genética , Macrófagos Associados a Tumor/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Células HEK293 , Humanos , Interferon gama/metabolismo , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Camundongos Knockout , Nicotinamida Fosforribosiltransferase/metabolismo , Células RAW 264.7 , RNA-Seq , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Células THP-1 , Macrófagos Associados a Tumor/metabolismo , Regulação para Cima , Efeito Warburg em Oncologia
5.
Cells ; 10(5)2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922837

RESUMO

Interactions between neoplastic and immune cells taking place in tumors drive cancer regulatory mechanisms both in humans and animals. IFN-λ, a potent antiviral factor, is also secreted in the tumor; however, its role in tumor development is still unclear. In our study, we investigate the influence of IFN-λ on the canine mammary tumor (CMT) cell survival and their metastatic potential in vitro. First, we examined, by Western blot, the expression of the IFN-λ receptor complex in three CMT cell lines (P114, CMT-U27 and CMT-U309). We showed that only two cell lines (P114 and CMT-U27) express both (IL-28RA and IL-10Rb) receptor subunits and respond to IFN-λ treatment by STAT phosphorylation and the expression of interferon-stimulated genes. Using MTT, crystal violet and annexin-V assays, we showed a minimal role of IFN-λ in CMT viability. However, IFN-λ administration had a contradictory effect on cell migration in the scratch test, namely, it increased P114 and decreased CMT-U27 motility. Moreover, we demonstrated that this process is related to the expression of extracellular matrix metalloproteinases and their inhibitors; furthermore, it is independent of Akt and ERK signaling pathways. To conclude, we showed that IFN-λ activity is reliant on the expression of two receptor subunits and tumor type, but further investigations are needed.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interferons/farmacologia , Neoplasias Mamárias Animais/patologia , Inibidores de Metaloproteinases de Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Receptores de Interferon/metabolismo , Receptores de Interleucina-10/metabolismo , Animais , Antineoplásicos/farmacologia , Cães , Feminino , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/metabolismo , Metaloproteinases da Matriz/genética , Receptores de Interferon/genética , Receptores de Interleucina-10/genética
6.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806448

RESUMO

Lambda interferons mediate antiviral immunity by inducing interferon-stimulated genes (ISGs) in epithelial tissues. A common variant rs368234815TT/∆G creating functional gene from an IFNL4 pseudogene is associated with the expression of major ISGs in the liver but impaired clearance of hepatitis C. To explain this, we compared Halo-tagged and non-tagged IFNL3 and IFNL4 signaling in liver-derived cell lines. Transfection with non-tagged IFNL3, non-tagged IFNL4 and Halo-tagged IFNL4 led to a similar degree of JAK-STAT activation and ISG induction; however, the response to transfection with Halo-tagged IFNL3 was lower and delayed. Transfection with non-tagged IFNL3 or IFNL4 induced no transcriptome change in the cells lacking either IL10R2 or IFNLR1 receptor subunits. Cytosolic overexpression of signal peptide-lacking IFNL3 or IFNL4 in wild type cells did not interfere with JAK-STAT signaling triggered by interferons in the medium. Finally, expression profile changes induced by transfection with non-tagged IFNL3 and IFNL4 were highly similar. These data do not support the hypothesis about IFNL4-specific non-canonical signaling and point out that functional studies conducted with tagged interferons should be interpreted with caution.


Assuntos
Hepatócitos/imunologia , Hepatócitos/metabolismo , Interferons/genética , Interferons/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Linhagem Celular , Expressão Gênica , Técnicas de Inativação de Genes , Células Hep G2 , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Interferons/deficiência , Subunidade beta de Receptor de Interleucina-10/deficiência , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/metabolismo , Interleucinas/deficiência , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Transfecção
7.
Science ; 371(6536)2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33766856

RESUMO

The pathways that lead to the development of tissue-resident lymphocytes, including liver type 1 innate lymphoid cells (ILC1s), remain unclear. We show here that the adult mouse liver contains Lin-Sca-1+Mac-1+ hematopoietic stem cells derived from the fetal liver. This population includes Lin-CD122+CD49a+ progenitors that can generate liver ILC1s but not conventional natural killer cells. Interferon-γ (IFN-γ) production by the liver ILC1s themselves promotes the development of these cells in situ, through effects on their IFN-γR+ liver progenitors. Thus, an IFN-γ-dependent loop drives liver ILC1 development in situ, highlighting the contribution of extramedullary hematopoiesis to regional immune composition within the liver.


Assuntos
Interferon gama/metabolismo , Fígado/citologia , Fígado/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Animais , Hematopoese Extramedular , Imunidade Inata , Interferon gama/genética , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Linfopoese , Camundongos , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Transdução de Sinais , Proteínas com Domínio T/metabolismo
8.
Cancer Res ; 81(8): 2171-2183, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33558334

RESUMO

Ewing sarcoma is the second most common pediatric bone cancer, with a 5-year survival rate for metastatic disease of only 20%. Recent work indicates that survival is strongly correlated with high levels of tumor-infiltrating lymphocytes (TIL), whose abundance is associated with IFN-inducible chemokines CXCL10 and CCL5. However, the tumor-intrinsic factors that drive chemokine production and TIL recruitment have not been fully elucidated. We previously showed that ubiquitin-specific protease 6 (USP6) directly deubiquitinates and stabilizes Jak1, thereby inducing an IFN signature in Ewing sarcoma cells. Here, we show that this gene set comprises chemokines associated with immunostimulatory, antitumorigenic functions, including CXCL10 and CCL5. USP6 synergistically enhanced chemokine production in response to exogenous IFN by inducing surface upregulation of IFNAR1 and IFNGR1. USP6-expressing Ewing sarcoma cells stimulated migration of primary human monocytes and T lymphocytes and triggered activation of natural killer (NK) cells in vitro. USP6 inhibited Ewing sarcoma xenograft growth in nude but not NSG mice and was accompanied by increased intratumoral chemokine production and infiltration and activation of NK cells, dendritic cells, and macrophages, consistent with a requirement for innate immune cells in mediating the antitumorigenic effects of USP6. High USP6 expression in patients with Ewing sarcoma was associated with chemokine production, immune infiltration, and improved survival. This work reveals a previously unrecognized tumor-suppressive function for USP6, which engenders an immunostimulatory microenvironment through pleiotropic effects on multiple immune lineages. This further raises the possibility that USP6 activity may be harnessed to create a "hot" tumor microenvironment in immunotherapy. SIGNIFICANCE: This study reveals a novel tumor-suppressive function for USP6 by inducing an immunostimulatory microenvironment, suggesting that USP6 activity may be exploited to enhance immunotherapy regimens.


Assuntos
Neoplasias Ósseas/genética , Linfócitos do Interstício Tumoral , Sarcoma de Ewing/genética , Proteínas Supressoras de Tumor/fisiologia , Ubiquitina Tiolesterase/fisiologia , Animais , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Movimento Celular/efeitos dos fármacos , Quimiocina CCL5/biossíntese , Quimiocina CXCL10/biossíntese , Células Dendríticas/efeitos dos fármacos , Humanos , Imunoterapia , Interferons/farmacologia , Janus Quinase 1/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Receptor de Interferon alfa e beta/metabolismo , Receptores de Interferon/metabolismo , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/mortalidade , Microambiente Tumoral/imunologia , Ubiquitina Tiolesterase/imunologia , Ubiquitina Tiolesterase/metabolismo , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Biochem Biophys Res Commun ; 545: 14-19, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33529805

RESUMO

Paneth cells and Lgr5+ intestinal stem cells (Lgr5+ ISCs) constitute the stem cell niche and maintain small intestinal epithelial integrity by recognizing various niche factors derived from subepithelial cells and external antigens. Although it has been known that interferon-γ (IFN-γ), a Th1 cytokine, is associated with intestinal epithelial disruption during inflammation as a niche factor, dynamics of Paneth cells and Lgr5+ ISCs in response to IFN-γ remain to be understood. Here we show that CAG-tdTomato;Lgr5-EGFP (CT-LE) mice generated in this study enable to identify Paneth cells and Lgr5+ ISCs separately by fluorescence signals. Lgr5+ ISCs underwent cell death a little earlier than Paneth cells in response to IFN-γ by simultaneous tracking using CT-LE mice. In addition, the timing of cell death in most Paneth cells overlapped with Lgr5+ ISCs, suggesting that Paneth cell depletion is induced directly by IFN-γ. Taken together, we established a novel simultaneous stem cell niche tracking method and clarified the involvement of both Paneth cells and Lgr5+ ISCs in stem cell niche damage induced by IFN-γ, further contribute to understanding the mechanism for maintaining intestinal homeostasis by stem cell niche.


Assuntos
Interferon gama/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Celulas de Paneth/efeitos dos fármacos , Celulas de Paneth/patologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Sistemas Computacionais , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Interferon gama/fisiologia , Mucosa Intestinal/fisiologia , Camundongos , Camundongos Transgênicos , Celulas de Paneth/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Interferon/metabolismo , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/fisiologia , Células-Tronco/fisiologia
10.
Nat Commun ; 12(1): 723, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526787

RESUMO

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.


Assuntos
Adenocarcinoma/secundário , Neoplasias Ósseas/secundário , Células-Tronco Mesenquimais/patologia , Neoplasias da Próstata/patologia , Receptores de Interferon/metabolismo , Ácidos Aminossalicílicos/farmacologia , Ácidos Aminossalicílicos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Benzenossulfonatos/farmacologia , Benzenossulfonatos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Meios de Cultivo Condicionados/metabolismo , Modelos Animais de Doenças , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Humanos , Interferons/genética , Interferons/metabolismo , Masculino , Camundongos Knockout , Osteoblastos/patologia , Cultura Primária de Células , Neoplasias da Próstata/tratamento farmacológico , RNA Interferente Pequeno/metabolismo , Receptores de Interferon/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Tíbia/patologia
11.
Cell Immunol ; 359: 104241, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33158544

RESUMO

Bearing in mind that mast cell contribution to viral clearance is still not fully understood, in this study, we evaluated the effect of Toll-like receptor (TLR)7 viral single-stranded ribonucleic acid (ssRNA) mimic ligand, namely resiquimod (R)848, on mast cell phenotype and activity. We demonstrated that rat peritoneal mast cells exhibit surface and intracellular expression of ssRNA-specific TLR7 molecule, and that mimic ligand switches the self-expression of this receptor. We also detected other proteins associated with the cellular antiviral response: interferon-alpha receptor 1 (IFNAR1), interferon-gamma receptor 1 (IFNGR1), and major histocompatibility complex I (MHC I). Moreover, we showed that R848 caused the decrease of all molecule's expression after prolonged incubation. Interestingly, we found that R848 induced the increase of high-affinity IgE receptor (FcεRI) expression. Finally, we documented that TLR7 ligand-stimulated mast cells synthesize/release interferon (IFN)-α and -ß, tumor necrosis factor (TNF), and chemokines CCL3, CXCL8, as well as pro-inflammatory lipid mediators. Our findings confirm that mast cells may respond to TLR7 ligand by altering their phenotype and synthesizing mediators and could serve as active participants in the antiviral immune response.


Assuntos
Imidazóis/farmacologia , Mastócitos/metabolismo , Animais , Células Cultivadas , Feminino , Imidazóis/metabolismo , Complexo Principal de Histocompatibilidade , Mastócitos/efeitos dos fármacos , Fenótipo , Ratos , Ratos Wistar , Receptor de Interferon alfa e beta/metabolismo , Receptores de IgE , Receptores de Interferon/metabolismo , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/metabolismo
12.
Life Sci Alliance ; 4(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33158978

RESUMO

Compared with the ubiquitous expression of type I (IFNα and IFNß) interferon receptors, type III (IFNλ) interferon receptors are mainly expressed in epithelial cells of mucosal barriers of the of the intestine and respiratory tract. Consequently, IFNλs are important for innate pathogen defense in the lung and intestine. IFNλs also determine the outcome of hepatitis C virus (HCV) infections, with IFNλ4 inhibiting spontaneous clearance of HCV. Because viral clearance is dependent on T cells, we explored if IFNλs can directly bind to and regulate human T cells. We found that human B cells and CD8+ T cells express the IFNλ receptor and respond to IFNλs, including IFNλ4. IFNλs were not inhibitors but weak stimulators of B- and T-cell responses. Furthermore, IFNλ4 showed neither synergistic nor antagonistic effects in co-stimulatory experiments with IFNλ1 or IFNα. Multidimensional flow cytometry of cells from liver biopsies of hepatitis patients from IFNλ4-producers showed accumulation of activated CD8+ T cells with a central memory-like phenotype. In contrast, CD8+ T cells with a senescent/exhausted phenotype were more abundant in IFNλ4-non-producers. It remains to be elucidated how IFNλ4 promotes CD8 T-cell responses and inhibits the host immunity to HCV infections.


Assuntos
Antígenos CD19/metabolismo , Linfócitos B/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Hepacivirus , Hepatite C/sangue , Interleucinas/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Adolescente , Adulto , Idoso , Doadores de Sangue , Feminino , Hepatite C/patologia , Hepatite C/virologia , Humanos , Interferon-alfa/farmacologia , Interferons/farmacologia , Masculino , Pessoa de Meia-Idade , Receptores de Interferon/metabolismo , Adulto Jovem
13.
J Pharmacol Exp Ther ; 376(1): 21-28, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33158943

RESUMO

Immune checkpoint inhibitors have emerged as a frontline treatment of a variety of malignancies. However, only a subset of patients respond to these therapies, and many initial responders eventually develop resistance, leading to tumor relapse. Programmed death protein 1 is one of the checkpoint inhibitors that is expressed on activated T cells and suppresses the antitumor immune response when binding to its ligand, programmed death ligand 1, on tumor cells. Previous studies indicated that loss-of-function mutations in the IFN-γ pathway could result in acquired resistance to immune checkpoint inhibitors in human patients with cancer. Here, we investigated the effects of the IFN-γ receptor downexpression on the response to an anti-PD-1 antibody (αPD1) in a murine colorectal cancer model and the underlying mechanisms of resistance. IFN-γ receptor (IFNGR) 1 was knocked down in MC38 cells, a murine colon adenocarcinoma cell line using IFNGR1 short hairpin RNA (shRNA) lentiviral particles. Then, MC38 IFNGR1 knockdown (KD) cells and negative control (SC) cells were used in this study. In the C57BL/6 xenograft model, the KD tumor demonstrated resistance to αPD1 in comparison with SC cells. The observed treatment resistance might be associated with reduced tumor-infiltrating immune cells (TILs). When mixed, the resistant (KD) and control cells (SC) grew in spatially separated tumor areas, and αPD1 did not impact this pattern of spatial distribution. Our findings have proved that downregulation of the IFNGR1 endowed resistance to αPD1 and provided the potential mechanisms involving the TILs. SIGNIFICANCE STATEMENT: Immunological checkpoint blockades have achieved substantial efficacy in a variety of tumors. However, only a subset of patients respond to these therapies, and innate and acquired resistance is widely present. Our study found that the downregulation of the IFN-γ receptor caused resistance to an anti-PD-1 antibody in a murine colorectal cancer model associated with the reduced tumor-infiltrating lymphocytes. Our findings have substantial implications for improving the efficacy of checkpoint blockades.


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Interferon/genética , Adenocarcinoma/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Regulação para Baixo , Feminino , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interferon/metabolismo
14.
Front Immunol ; 11: 606489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33281831

RESUMO

Interferons (IFNs) are a family of cytokines with the unique ability to induce cell intrinsic programs that enhance resistance to viral infection. Induction of an antiviral state at the cell, tissue, organ, and organismal level is performed by three distinct IFN families, designated as Type-I, Type-II, and Type-III IFNs. Overall, there are 21 human IFNs, (16 type-I, 12 IFNαs, IFNß, IFNϵ, IFNκ, and IFNω; 1 type-II, IFNγ; and 4 type-III, IFNλ1, IFNλ2, IFNλ3, and IFNλ4), that induce pleotropic cellular activities essential for innate and adaptive immune responses against virus and other pathogens. IFN signaling is initiated by binding to distinct heterodimeric receptor complexes. The three-dimensional structures of the type-I (IFNα/IFNAR1/IFNAR2), type-II (IFNγ/IFNGR1/IFNGR2), and type-III (IFNλ3/IFNλR1/IL10R2) signaling complexes have been determined. Here, we highlight similar and unique features of the IFNs, their cell surface complexes and discuss their role in inducing downstream IFN signaling responses.


Assuntos
Interferons/metabolismo , Receptores de Interferon/metabolismo , Transdução de Sinais , Animais , Humanos , Interferons/química , Ligantes , Camundongos , Modelos Moleculares , Conformação Proteica , Receptores de Interferon/química , Especificidade da Espécie , Relação Estrutura-Atividade
15.
J Immunol ; 205(10): 2629-2639, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33067379

RESUMO

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has profound activity in chronic lymphocytic leukemia (CLL) but limited curative potential by itself. Residual signaling pathways that maintain survival of CLL cells might be targeted to improve ibrutinib's therapeutic activity, but the nature of these pathways is unclear. Ongoing activation of IFN receptors in patients on ibrutinib was suggested by the presence of type I and II IFN in blood together with the cycling behavior of IFN-stimulated gene (ISG) products when IFN signaling was blocked intermittently with the JAK inhibitor ruxolitinib. IFN signaling in CLL cells from human patients was not prevented by ibrutinib in vitro or in vivo, but ISG expression was significantly attenuated in vitro. ISGs such as CXCL10 that require concomitant activation of NF-κB were decreased when this pathway was inhibited by ibrutinib. Other ISGs, exemplified by LAG3, were decreased as a result of inhibited protein translation. Effects of IFN on survival remained intact as type I and II IFN-protected CLL cells from ibrutinib in vitro, which could be prevented by ruxolitinib and IFNR blocking Abs. These observations suggest that IFNs may help CLL cells persist and specific targeting of IFN signaling might deepen clinical responses of patients on ibrutinib.


Assuntos
Adenina/análogos & derivados , Interferon Tipo I/metabolismo , Interferon gama/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/farmacologia , Adenina/farmacologia , Adenina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/imunologia , Piperidinas/uso terapêutico , Cultura Primária de Células , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Receptores de Interferon/antagonistas & inibidores , Receptores de Interferon/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Tumorais Cultivadas
16.
Front Immunol ; 11: 577546, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101303

RESUMO

Japanese encephalitis virus (JEV) exposure or vaccination could elicit cross-reactive CD8 T cell immunity against heterologous flaviviruses in humans. In addition, cross-reactive CD8 T cells induced by dengue virus (DENV) have been shown to play a protective role against Zika virus (ZIKV). However, how JEV exposure or vaccination affects ZIKV infection in humans remains unclear. In this report, epitope prediction algorithms were used to predict the cross-reactive CD8 T cell epitope restricted to human HLA between JEV and ZIKV. We found that these predicted CD8 T cell epitopes are immunogenic and cross-reactive in humanized HLA transgenic mice. Moreover, JEV vaccine immunization provided cross-protection against ZIKV infection. Furthermore, CD8 T cells were involved in the protection against ZKIV infection in vivo. Our results have an important clinical implication that vaccination with JEV SA14-14-2 may provide protection against ZIKV infection in humans.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/imunologia , Imunidade Celular , Imunogenicidade da Vacina , Vacinas contra Encefalite Japonesa/farmacologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Chlorocebus aethiops , Cricetinae , Reações Cruzadas , Modelos Animais de Doenças , Epitopos de Linfócito T/metabolismo , Antígeno HLA-A2/genética , Antígeno HLA-A2/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Epitopos Imunodominantes , Vacinas contra Encefalite Japonesa/administração & dosagem , Células K562 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Vacinação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/farmacologia , Células Vero , Zika virus/patogenicidade , Infecção por Zika virus/imunologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia
17.
Diabetes ; 69(12): 2630-2641, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32994273

RESUMO

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1 a-KO ) enhanced mitochondrial function and accelerated tricarboxylic acid cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1 a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon-γ activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.


Assuntos
Tecido Adiposo/metabolismo , Regulação da Expressão Gênica/fisiologia , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Fator de Transcrição STAT1/metabolismo , Adipócitos/metabolismo , Animais , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Feminino , Glucose/metabolismo , Homeostase/fisiologia , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Interferência de RNA , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Fator de Transcrição STAT1/genética
18.
J Immunol ; 205(6): 1601-1607, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32796026

RESUMO

Secondary Streptococcus pneumoniae infection is a significant cause of morbidity and mortality during influenza epidemics and pandemics. Multiple pathogenic mechanisms, such as lung epithelial damage and dysregulation of neutrophils and alveolar macrophages (AMs), have been suggested to contribute to the severity of disease. However, the fundamental reasons for influenza-induced susceptibility to secondary bacterial pneumonia remain unclear. In this study, we revisited these controversies over key pathogenic mechanisms in a lethal model of secondary bacterial pneumonia with an S. pneumoniae strain that is innocuous to mice in the absence of influenza infection. Using a series of in vivo models, we demonstrate that rather than a systemic suppression of immune responses or neutrophil function, influenza infection activates IFN-γR signaling and abrogates AM-dependent bacteria clearance and thereby causes extreme susceptibility to pneumococcal infection. Importantly, using mice carrying conditional knockout of Ifngr1 gene in different myeloid cell subsets, we demonstrate that influenza-induced IFN-γR signaling in AMs impairs their antibacterial function, thereby enabling otherwise noninvasive S. pneumoniae to cause deadly pneumonia.


Assuntos
Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Macrófagos Alveolares/fisiologia , Infecções por Orthomyxoviridae/imunologia , Pneumonia Pneumocócica/imunologia , Receptores de Interferon/metabolismo , Streptococcus pneumoniae/fisiologia , Animais , Coinfecção , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interferon/genética , Transdução de Sinais
19.
Int J Mol Sci ; 21(16)2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32824561

RESUMO

Prolidase [EC 3.4.13.9], known as PEPD, cleaves di- and tripeptides containing carboxyl-terminal proline or hydroxyproline. For decades, prolidase has been thoroughly investigated, and several mechanisms regulating its activity are known, including the activation of the ß1-integrin receptor, insulin-like growth factor 1 receptor (IGF-1) receptor, and transforming growth factor (TGF)-ß1 receptor. This process may result in increased availability of proline in the mitochondrial proline cycle, thus making proline serve as a substrate for the resynthesis of collagen, an intracellular signaling molecule. However, as a ligand, PEPD can bind directly to the epidermal growth factor receptor (EGFR, epidermal growth factor receptor 2 (HER2)) and regulate cellular metabolism. Recent reports have indicated that PEPD protects p53 from uncontrolled p53 subcellular activation and its translocation between cellular compartments. PEPD also participates in the maturation of the interferon α/ß receptor by regulating its expression. In addition to the biological effects, prolidase demonstrates clinical significance reflected in the disease known as prolidase deficiency. It is also known that prolidase activity is affected in collagen metabolism disorders, metabolic, and oncological conditions. In this article, we review the latest knowledge about prolidase and highlight its biological function, and thus provide an in-depth understanding of prolidase as a dipeptidase and protein regulating the function of key biomolecules in cellular metabolism.


Assuntos
Dipeptidases/metabolismo , Animais , Dipeptidases/genética , Receptores ErbB/metabolismo , Humanos , Receptores de Interferon/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
20.
Arthritis Rheumatol ; 72(10): 1707-1720, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32500632

RESUMO

OBJECTIVE: Pristane-induced lupus is associated with nonresolving inflammation and deficiency of proresolving macrophages. Proresolving nonclassic macrophages (NCMs) are less responsive to type I interferon (IFN) than classic macrophages (CMs; which are proinflammatory), reflecting their relative expression levels of the type I IFN receptor (IFNAR). This study was undertaken to investigate the regulation of IFNAR expression in macrophages. METHODS: We carried out gene expression profiling of purified CMs and NCMs from mice treated with pristane (which develop lupus) or mineral oil (non-lupus controls). Macrophage differentiation and IFNAR expression were examined in mice treated with NF-E2-related factor 2 (Nrf2) activators and inhibitors and in Nrf2-deficient mice. Nrf2 activity was also assessed in blood cells from patients with systemic lupus erythematosus (SLE). Significant differences were determined by Student's t-test. RESULTS: RNA sequencing revealed increased expression of genes regulated by the transcription factor Nrf2 in NCMs from mineral oil-treated versus pristane-treated mice and in NCMs versus CMs. The Nrf2 activator CDDO-imidazole (CDDO-Im) decreased CMs (P < 0.0001) and promoted the development of proresolving NCMs (P = 0.06), whereas the Nrf2 inhibitor brusatol increased CMs (P < 0.05) and decreased NCMs (P < 0.001). CDDO-Im decreased Ifnar1 (P < 0.001) and IFN-stimulated gene (ISG) expression in macrophages and alleviated oxidative stress (P < 0.05), whereas brusatol had the opposite effect (P < 0.01). Moreover, Ifnar1 and ISG expression levels were higher in Nrf2-knockout mice than controls (P < 0.05). As seen in mice with lupus, SLE patients showed evidence of low Nrf2 activity. CONCLUSION: Our findings indicate that Nrf2 activation favors the resolution of chronic inflammation in lupus. Since autoantibody production and lupus nephritis depend on IFNAR signaling, the ability of Nrf2 activators to repolarize macrophages and reduce the INF signature suggests that these agents may warrant consideration for treating lupus.


Assuntos
Polaridade Celular/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/metabolismo , Macrófagos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Receptores de Interferon/metabolismo , Animais , Expressão Gênica , Imidazóis/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Quassinas/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...