Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.097
Filtrar
1.
J Insect Sci ; 21(1)2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33511414

RESUMO

Insect innate immunity is initiated by the special recognition and binding of the foreign pathogens, which is accomplished by the pattern recognition receptors (PRRs). As an important type of PRRs, C-type lectins (CTLs) play various roles in insect innate immunity, including pathogen recognition, stimulation of prophenoloxidase, regulation of cellular immunity and so on. In this study, we have cloned the full-length cDNA of a CTL gene named CTL-S6 from the silkworm, Bombyx mori. The open reading frame (ORF) of B. mori CTL-S6 encodes 378 amino acids, which contain a secretion signal peptide. The mRNA of CTL-S6 exhibited the highest transcriptional level in the midgut. Its transcriptional level increased dramatically in fat body and hemocytes upon Escherichia coli or Micrococcus luteus challenge. Purified recombinant CTL-S6 could bind to bacterial cell wall components, including peptidoglycan (PGN, from Bacillus subtilis) and lipopolysaccharide (LPS, from E. coli 0111:B4), and recombinant CTL-S6 was involved in the encapsulation and melanization of hemocytes. Furthermore, the addition of recombinant CTL-S6 to the hemolymph of silkworm resulted in a significant increase in phenoloxidase activity. Overall, our results indicated that B. mori CTL-S6 may serve as a PRR for the recognition of foreign pathogens, prophenoloxidase pathway stimulation and involvement in the innate immunity.


Assuntos
Escherichia coli/fisiologia , Imunidade Inata/genética , Proteínas de Insetos/genética , Lectinas Tipo C/genética , Micrococcus luteus/fisiologia , Receptores de Reconhecimento de Padrão/genética , Transcrição Genética , Sequência de Aminoácidos , Animais , Bombyx , Corpo Adiposo/imunologia , Perfilação da Expressão Gênica , Hemócitos/imunologia , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Lectinas Tipo C/química , Lectinas Tipo C/metabolismo , Filogenia , Receptores de Reconhecimento de Padrão/química , Receptores de Reconhecimento de Padrão/metabolismo , Alinhamento de Sequência
2.
Viruses ; 13(1)2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33374950

RESUMO

Virus-induced inflammation plays a critical role in determining the clinical outcome of an acute respiratory virus infection. We have shown previously that the administration of immunobiotic Lactobacillus plantarum (Lp) directly to the respiratory tract prevents lethal inflammatory responses to subsequent infection with a mouse respiratory virus pathogen. While Lp-mediated protective responses involve non-redundant contributions of both Toll-like receptor 2 (TLR2) and NOD2, the cellular basis of these findings remains unclear. Here, we address the impact of Lp and its capacity to suppress inflammation in virus-infected respiratory epithelial cells in two cell culture models. We found that both MLE-12 cells and polarized mouse tracheal epithelial cells (mTECs) were susceptible to infection with Influenza A and released proinflammatory cytokines, including CCL2, CCL5, CXCL1, and CXCL10, in response to replicating virus. MLE-12 cells express NOD2 (81 ± 6.3%) and TLR2 (19 ± 4%), respond to Lp, and are TLR2-specific, but not NOD2-specific, biochemical agonists. By contrast, we found that mTECs express NOD2 (81 ± 17%) but minimal TLR2 (0.93 ± 0.58%); nonetheless, mTECs respond to Lp and the TLR2 agonist, Pam2CSK4, but not NOD2 agonists or the bifunctional TLR2-NOD2 agonist, CL-429. Although MLE-12 cells and mTECS were both activated by Lp, little to no cytokine suppression was observed in response to Lp followed by virus infection via a protocol that replicated experimental conditions that were effective in vivo. Further study and a more complex approach may be required to reveal critical factors that suppress virus-induced inflammatory responses.


Assuntos
Reações Cruzadas/imunologia , Inflamação/etiologia , Lactobacillus plantarum/fisiologia , Probióticos , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/metabolismo , Imunofenotipagem , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Ligantes , Camundongos , Camundongos Knockout , Receptores de Reconhecimento de Padrão/metabolismo , Mucosa Respiratória/microbiologia , Mucosa Respiratória/patologia , Receptor 2 Toll-Like/metabolismo , Viroses/complicações , Viroses/virologia , Perda de Peso
3.
Scand J Immunol ; 92(5): e12957, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32767789

RESUMO

Bone marrow haematopoietic stem and progenitor cells (HSPCs) express pattern recognition receptors such as Toll-like receptors (TLRs) to sense microbial products and activation of these innate immune receptors induces cytokine expression and redirects bone marrow haematopoiesis towards the increased production of myeloid cells. Secreted cytokines by HSPCs in response to TLR ligands can act in an autocrine or paracrine manner to regulate haematopoiesis. Moreover, tonic activation of HSPCs by microbiota-derived compounds might educate HSPCs to produce superior myeloid cells equipped with innate memory responses to combat pathogens. While haematopoietic stem cell activation through TLRs meets the increased demand for blood leucocytes to protect the host against infection, persistent exposure to inflammatory cytokines or microbial products might impair their function and even induce malignant transformation. This review highlights the potential outcomes of HSPCs in response to TLR ligands.


Assuntos
Células da Medula Óssea/imunologia , Células-Tronco Hematopoéticas/imunologia , Microbiota/imunologia , Células Mieloides/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/microbiologia , Citocinas/imunologia , Citocinas/metabolismo , Hematopoese/imunologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/microbiologia , Humanos , Células Mieloides/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo
4.
Cells ; 9(9)2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32854433

RESUMO

Coronaviruses (CoVs) are a diverse family of the enveloped human and animal viruses reported as causative agents for respiratory and intestinal infections. The high pathogenic potential of human CoVs, including SARS-CoV, MERS-CoV and SARS-CoV-2, is closely related to the invasion mechanisms underlying the attachment and entry of viral particles to the host cells. There is increasing evidence that sialylated compounds of cellular glycocalyx can serve as an important factor in the mechanism of CoVs infection. Additionally, the sialic acid-mediated cross-reactivity with the host immune lectins is known to exert the immune response of different intensity in selected pathological stages. Here, we focus on the last findings in the field of glycobiology in the context of the role of sialic acid in tissue tropism, viral entry kinetics and immune regulation in the CoVs infections.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Citocinas/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Ácido N-Acetilneuramínico/metabolismo , Pneumonia Viral/imunologia , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/imunologia , Animais , Infecções por Coronavirus/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/virologia , Receptores de Reconhecimento de Padrão/metabolismo , Síndrome Respiratória Aguda Grave/virologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Receptores Toll-Like/metabolismo , Internalização do Vírus
5.
J Cancer Res Ther ; 16(3): 405-409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719244

RESUMO

Activation of inflammasomes has a decisive role in host defense mechanism against pathogens and other intracellular risk factors, but recently, it has been revealed that they play a significant role in the pathogenesis of several diseases, including cancer. Nod-like receptor protein 3 (NLRP3) inflammasome, the best-studied inflammasome, has contrasting roles in cancer development and progressions. In head-and-neck cancers, the upregulated level of NLRP3 promotes tumor progression. The main objective of this review is to provide current knowledge on the involvement of NLRP3 inflammasome in head-and-neck cancers. Deeper understanding of the biology of this dynamic protein complex provides new scope for the development of more effective anticancer therapies.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Imunidade Inata , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais
6.
Sci Rep ; 10(1): 7604, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32371942

RESUMO

The cGAS-STING pathway is a major mechanism that mammalian cells utilize to detect cytoplasmic dsDNA from incoming viruses, bacteria, or self. CYCLIC GMP-AMP SYNTHASE (cGAS) is the sensor protein that directly binds dsDNAs. cGAS synthesizes cyclic GMP-AMP (cGAMP), which binds to the adaptor STIMULATOR OF INTERFERON GENES (STING), activating an INTERFERON REGULATORY FACTOR 3 (IRF3)-mediated immune response. Constitutive activation can result in interferonopathies such as Aicardi-Goutieres Syndrome (AGS) or other lupus-like autoimmune disorders. While inhibitors targeting mouse or human cGAS have been reported, the identification of a small molecule that targets both homologs of cGAS has been challenging. Here, we show that RU.521 is capable of potently and selectively inhibiting mouse and human cGAS in cell lines and human primary cells. This inhibitory activity requires the presence of cGAS, but it cannot suppress an immune response in cells activated by RNA, Toll-like receptor ligands, cGAMP, or recombinant interferon. Importantly, when RU.521 is applied to cells, the production of dsDNA-induced intracellular cGAMP is suppressed in a dose-dependent manner. Our work validates the use of RU.521 for probing DNA-induced innate immune responses and underscores its potential as an ideal scaffold towards pre-clinical development, given its potency against human and mouse cGAS.


Assuntos
Citocinas/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Nucleotídeos Cíclicos/metabolismo , Nucleotidiltransferases/antagonistas & inibidores , Animais , Benzofuranos/farmacologia , Linhagem Celular , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Imunomodulação/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Modelos Biológicos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Nucleotidiltransferases/metabolismo , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Nat Commun ; 11(1): 1913, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312989

RESUMO

The TAGAP gene locus has been linked to several infectious diseases or autoimmune diseases, including candidemia and multiple sclerosis. While previous studies have described a role of TAGAP in T cells, much less is known about its function in other cell types. Here we report that TAGAP is required for Dectin-induced anti-fungal signaling and proinflammatory cytokine production in myeloid cells. Following stimulation with Dectin ligands, TAGAP is phosphorylated by EPHB2 at tyrosine 310, which bridges proximal Dectin-induced EPHB2 activity to downstream CARD9-mediated signaling pathways. During Candida albicans infection, mice lacking TAGAP mount defective immune responses, impaired Th17 cell differentiation, and higher fungal burden. Similarly, in experimental autoimmune encephalomyelitis model of multiple sclerosis, TAGAP deficient mice develop significantly attenuated disease. In summary, we report that TAGAP plays an important role in linking Dectin-induced signaling to the promotion of effective T helper cell immune responses, during both anti-fungal host defense and autoimmunity.


Assuntos
Antifúngicos/imunologia , Candidíase/imunologia , Diferenciação Celular , Proteínas Ativadoras de GTPase/química , Proteínas Ativadoras de GTPase/metabolismo , Receptor EphB2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Th17/metabolismo , Animais , Antifúngicos/farmacologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/microbiologia , Feminino , Proteínas Ativadoras de GTPase/genética , Humanos , Lectinas Tipo C/metabolismo , Masculino , Camundongos Knockout , Esclerose Múltipla/complicações , Esclerose Múltipla/imunologia , Fosforilação , Receptor EphB2/imunologia , Receptores Imunológicos , Receptores de Reconhecimento de Padrão/metabolismo , Células Th17/imunologia
8.
Mol Immunol ; 121: 20-27, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142955

RESUMO

To study the interrelationship between the signaling adaptors of innate pattern recognition receptor (PRR) pathways including toll-like receptor (TLR), retinoic acid-inducible gene-1-like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and cytoplasmic DNA recognition receptors (CDR) pathways. The coding genes of porcine TRIF, MAVS, STING, MyD88, RIPK2, and ASC were isolated from PK15 cells. Phylogenetic analysis of the six adaptor proteins in pig, cattle, goat, horse, human, mouse, chicken, and duck performed by MEGA 5.05 showed that these adaptors have slightly different similarity across species. The expression of these proteins in transfected cells were detected by both Western blotting and confocal microscopy. All six adaptors were visualized in cytoplasm but with different distribution patterns. The activities of the six adaptors triggering NF-κB and ISRE signaling and downstream gene productions were examined by dual-luciferase reporter assay and real-time RT-PCR, respectively. The results showed that STING has an ability to activate ISRE signaling, MyD88, RIPK2 and ASC possess NF-κB signal activity, while TRIF and MAVS can activate both. Furthermore, the mutual signaling effects were assessed by NF-κB and ISRE dual-luciferase reporter assay in the co-expression experiments. STING was shown to enhance MAVS activated NF-κB signaling and MyD88 could heighten STING activated ISRE signaling. However, all other adaptors inhibited each other to varying degrees. The work provides a global insight of porcine innate immune signaling pathways and their interaction network.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Imunidade Inata , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/isolamento & purificação , Animais , Células HEK293 , Humanos , Filogenia , Receptores de Reconhecimento de Padrão/imunologia , Suínos
9.
Mol Pharmacol ; 97(5): 324-335, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173651

RESUMO

Skin serves not only as a protective barrier to microbial entry into the body but also as an immune organ. The outer layer, the epidermis, is composed predominantly of keratinocytes, which can be stimulated to produce proinflammatory mediators. Although some inflammation is useful to defend against infection, excessive or persistent inflammation can lead to the development of inflammatory skin diseases, such as psoriasis, a common skin disorder affecting approximately 2% of the US population. We have previously found that phosphatidylglycerol (PG) derived from soy can inhibit inflammation in a contact irritant ear edema mouse model. Here, we investigated the ability of soy PG to inhibit inflammatory mediator expression in response to activators of the pattern recognition receptors, toll-like receptor-2 (TLR2) and -4 (TLR4). We found that in epidermal keratinocytes, soy PG inhibited TLR2 and TLR4 activation and inflammatory mediator expression in response to a synthetic triacylated lipopeptide and lipopolysaccharide, respectively, as well as an endogenous danger-associated molecular pattern. However, at higher concentrations, soy PG alone enhanced the expression of some proinflammatory cytokines, suggesting a narrow therapeutic window for this lipid. Dioleoylphosphatidylglycerol (DOPG), but not dioleoylphosphatidylcholine, exerted a similar inhibitory effect, completely blocking keratinocyte inflammatory mediator expression induced by TLR2 and TLR4 activators as well as NFκB activation in a macrophage cell line (RAW264.7); however, DOPG was not itself proinflammatory even at high concentrations. Furthermore, DOPG had no effect on NFκB activation in response to a TLR7/8 agonist. Our results suggest that DOPG could be used to inhibit excessive skin inflammation. SIGNIFICANCE STATEMENT: Although inflammation is beneficial for clearing an infection, in some cases, the infection can be excessive and/or become chronic, thereby resulting in considerable tissue damage and pathological conditions. We show here that the phospholipid phosphatidylglycerol can inhibit the activation of toll-like receptors 2 and 4 of the innate immune system as well as the downstream inflammatory mediator expression in response to microbial component-mimicking agents in epidermal keratinocytes that form the physical barrier of the skin.


Assuntos
Mediadores da Inflamação/metabolismo , Queratinócitos/metabolismo , Padrões Moleculares Associados a Patógenos/farmacologia , Fosfatidilgliceróis/farmacologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Calgranulina B/farmacologia , Humanos , Imidazóis/farmacologia , Lipopeptídeos/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Células RAW 264.7 , Receptores de Reconhecimento de Padrão/metabolismo , Proteínas Recombinantes/farmacologia , Soja/química
10.
Curr Top Microbiol Immunol ; 425: 187-223, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32180018

RESUMO

Fungi are opportunistic pathogens that infect immunocompromised patients and are responsible for an estimated 1.5 million deaths every year. The antifungal innate immune response is mediated through the recognition of pathogen-associated molecular patterns (PAMPs) by the host's pattern recognition receptors (PRRs). PRRs are immune receptors that ensure the internalisation and the killing of fungal pathogens. They also mount the inflammatory response, which contributes to initiate and polarise the adaptive response, controlled by lymphocytes. Both the innate and adaptive immune responses are required to control fungal infections. The immune recognition of fungal pathogen primarily occurs at the interface between the membrane of innate immune cells and the fungal cell wall, which contains a number of PAMPs. This chapter will focus on describing the main mammalian PRRs that have been shown to bind to PAMPs from the fungal cell wall of the four main fungal pathogens: Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Pneumocystis jirovecii. We will describe these receptors, their functions and ligands to provide the reader with an overview of how the immune system recognises fungal pathogens and responds to them.


Assuntos
Parede Celular , Imunidade Inata , Micoses/imunologia , Micoses/microbiologia , Padrões Moleculares Associados a Patógenos , Receptores de Reconhecimento de Padrão , Animais , Parede Celular/imunologia , Parede Celular/metabolismo , Humanos , Micoses/metabolismo , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo
11.
BMC Biol ; 18(1): 32, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209106

RESUMO

BACKGROUND: Nuclear factor-κB (NF-κB) plays a prominent role in promoting inflammation and resistance to DNA damaging therapy. We searched for proteins that modulate the NF-κB response as a prerequisite to identifying novel factors that affect sensitivity to DNA damaging chemotherapy. RESULTS: Using streptavidin-agarose pull-down, we identified the DExD/H-box RNA helicase, DDX39B, as a factor that differentially interacts with κB DNA probes. Subsequently, using both RNA interference and CRISPR/Cas9 technology, we demonstrated that DDX39B inhibits NF-κB activity by a general mechanism involving inhibition of p65 phosphorylation. Mechanistically, DDX39B mediates this effect by interacting with the pattern recognition receptor (PRR), LGP2, a pathway that required the cellular response to cytoplasmic double-stranded RNA (dsRNA). From a functional standpoint, loss of DDX39B promoted resistance to alkylating chemotherapy in glioblastoma cells. Further examination of DDX39B demonstrated that its protein abundance was regulated by site-specific sumoylation that promoted its poly-ubiquitination and degradation. These post-translational modifications required the presence of the SUMO E3 ligase, PIASx-ß. Finally, genome-wide analysis demonstrated that despite the link to the PRR system, DDX39B did not generally inhibit interferon-stimulated gene expression, but rather acted to attenuate expression of factors associated with the extracellular matrix, cellular migration, and angiogenesis. CONCLUSIONS: These results identify DDX39B, a factor with known functions in mRNA splicing and nuclear export, as an RNA-binding protein that blocks a subset of the inflammatory response. While these findings identify a pathway by which DDX39B promotes sensitization to DNA damaging therapy, the data also reveal a mechanism by which this helicase may act to mitigate autoimmune disease.


Assuntos
RNA Helicases DEAD-box/genética , NF-kappa B/metabolismo , Receptores de Reconhecimento de Padrão/genética , Transdução de Sinais , Alquilação , Animais , RNA Helicases DEAD-box/metabolismo , Sondas de DNA , Tratamento Farmacológico , Humanos , Camundongos , Receptores de Reconhecimento de Padrão/metabolismo
12.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32024003

RESUMO

Pathogen-associated molecular patterns (PAMPs), microbe-associated molecular patterns (MAMPs), herbivore-associated molecular patterns (HAMPs), and damage-associated molecular patterns (DAMPs) are molecules produced by microorganisms and insects in the event of infection, microbial priming, and insect predation. These molecules are then recognized by receptor molecules on or within the plant, which activates the defense signaling pathways, resulting in plant's ability to overcome pathogenic invasion, induce systemic resistance, and protect against insect predation and damage. These small molecular motifs are conserved in all organisms. Fungi, bacteria, and insects have their own specific molecular patterns that induce defenses in plants. Most of the molecular patterns are either present as part of the pathogen's structure or exudates (in bacteria and fungi), or insect saliva and honeydew. Since biotic stresses such as pathogens and insects can impair crop yield and production, understanding the interaction between these organisms and the host via the elicitor-receptor interaction is essential to equip us with the knowledge necessary to design durable resistance in plants. In addition, it is also important to look into the role played by beneficial microbes and synthetic elicitors in activating plants' defense and protection against disease and predation. This review addresses receptors, elicitors, and the receptor-elicitor interactions where these components in fungi, bacteria, and insects will be elaborated, giving special emphasis to the molecules, responses, and mechanisms at play, variations between organisms where applicable, and applications and prospects.


Assuntos
Resistência à Doença , Plantas/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Alarminas/metabolismo , Animais , Padrões Moleculares Associados a Patógenos/metabolismo , Imunidade Vegetal , Proteínas de Plantas/metabolismo , Plantas/microbiologia , Plantas/parasitologia
13.
Adv Exp Med Biol ; 1223: 81-97, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030686

RESUMO

The involvement of inflammation in cancer progression is well-established. The immune system can play both tumor-promoting and -suppressive roles, and efforts to harness the immune system to help fight tumor growth are at the forefront of research. Of particular importance is the inflammatory profile at the site of the tumor, with respect to both the leukocyte population numbers, the phenotype of these cells, as well as the contribution of the tumor cells themselves. In this regard, the pro-inflammatory effects of pattern recognition receptor expression and activation in the tumor microenvironment have emerged as a relevant issue both for therapy and to understand tumor development.Pattern recognition receptors (PRRs) were originally recognized as components of immune cells, particularly innate immune cells, as detectors of pathogens. PRR signaling in immune cells activates them, inducing robust antimicrobial responses. In particular, toll-like receptors (TLRs) constitute a family of membrane-bound PRRs which can recognize pathogen-associated molecular patterns (PAMPs) carried by bacteria, virus, and fungi. In addition, PRRs can recognize products generated by stressed cells or damaged tissues, namely damage-associated molecular patterns or DAMPS. Taking into account the role of the immune system in fighting tumors together with the presence of immune cells in the microenvironment of different types of tumors, strategies to activate immune cells via PRR ligands have been envisioned as an anticancer therapeutic approach.In the last decades, it has been determined that PRRs are present and functional on nonimmune cells and that their activation in these cells contributes to the inflammation in the tumor microenvironment. Both tumor-promoting and antitumor effects have been observed when tumor cell PRRs are activated. This argues against nonspecific activation of PRR ligands in the tumor microenvironment as a therapeutic approach. Therefore, the use of PRR ligands for anticancer therapy might benefit from strategies that specifically deliver these ligands to immune cells, thus avoiding tumor cells in some settings. This review focuses on these aspects of TLR signaling in the tumor microenvironment.


Assuntos
Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Microambiente Tumoral , Humanos , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Microambiente Tumoral/imunologia
14.
Cell ; 180(3): 440-453.e18, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32032516

RESUMO

Recognition of microbe-associated molecular patterns (MAMPs) is crucial for the plant's immune response. How this sophisticated perception system can be usefully deployed in roots, continuously exposed to microbes, remains a mystery. By analyzing MAMP receptor expression and response at cellular resolution in Arabidopsis, we observed that differentiated outer cell layers show low expression of pattern-recognition receptors (PRRs) and lack MAMP responsiveness. Yet, these cells can be gated to become responsive by neighbor cell damage. Laser ablation of small cell clusters strongly upregulates PRR expression in their vicinity, and elevated receptor expression is sufficient to induce responsiveness in non-responsive cells. Finally, localized damage also leads to immune responses to otherwise non-immunogenic, beneficial bacteria. Damage-gating is overridden by receptor overexpression, which antagonizes colonization. Our findings that cellular damage can "switch on" local immune responses helps to conceptualize how MAMP perception can be used despite the presence of microbial patterns in the soil.


Assuntos
Arabidopsis/imunologia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Raízes de Plantas/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/microbiologia , Arabidopsis/efeitos da radiação , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/efeitos da radiação , Ascorbato Peroxidases/metabolismo , Ascorbato Peroxidases/efeitos da radiação , Flagelina/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Terapia a Laser/métodos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/efeitos da radiação , Microscopia Confocal , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/microbiologia , Raízes de Plantas/efeitos da radiação , Proteínas Quinases/metabolismo , Proteínas Quinases/efeitos da radiação , Receptores de Reconhecimento de Padrão/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Imagem com Lapso de Tempo
15.
Sci Rep ; 10(1): 1690, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015377

RESUMO

Dietary fibers have been shown to exert immune effects via interaction with pattern recognition receptors (PRR) such as toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors. Pectin is a dietary fiber that interacts with PRR depending on its chemical structure. Papaya pectin retains different chemical structures at different ripening stages. How this influence PRR signaling is unknown. The aim of this work was to determine how ripening influences pectin structures and their ability to interact with TLR2, 3, 4, 5 and 9, and NOD1 and 2. It was evaluated the interaction of the water-soluble fractions rich in pectin extracted from unripe to ripe papayas. The pectin extracted from ripe papayas activated all the TLR and, to a lesser extent, the NOD receptors. The pectin extracted from unripe papayas also activated TLR2, 4 and 5 but inhibited the activation of TLR3 and 9. The differences in pectin structures are the higher methyl esterification and smaller galacturonan chains of pectin from ripe papayas. Our finding might lead to selection of ripening stages for tailored modulation of PRR to support or attenuate immunity.


Assuntos
Carica/metabolismo , Pectinas/metabolismo , Receptores Imunológicos/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Fibras na Dieta/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo
16.
J Immunol ; 204(7): 1988-1997, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32094205

RESUMO

TLRs, a family of membrane-bound pattern recognition receptors found on innate immune cells, have been well studied in the context of cancer therapy. Activation of these receptors has been shown to induce inflammatory anticancer events, including differentiation and apoptosis, across a wide variety of malignancies. In contrast, intracellular pattern recognition receptors such as NOD-like receptors have been minimally studied. NOD2 is a member of the NOD-like receptor family that initiates inflammatory signaling in response to the bacterial motif muramyl dipeptide. In this study, we examined the influence of NOD2 in human acute myeloid leukemia (AML) cells, demonstrating that IFN-γ treatment upregulated the expression of NOD2 signaling pathway members SLC15A3 and SLC15A4, downstream signaling kinase RIPK2, and the NOD2 receptor itself. This priming allowed for effective induction of caspase-1-dependent cell death upon treatment with muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic ligand for NOD2. Furthermore, the combination of MTP-PE and IFN-γ on AML blasts generated an inflammatory cytokine profile and activated NK cells. In a murine model of AML, dual treatment with MTP-PE and IFN-γ led to a significant increase in mature CD27- CD11b+ NK cells as well as a significant reduction in disease burden and extended survival. These results suggest that NOD2 activation, primed by IFN-γ, may provide a novel therapeutic option for AML.


Assuntos
Apoptose/fisiologia , Leucemia Mieloide Aguda/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Interferon gama/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
18.
Adv Immunol ; 145: 95-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32081201

RESUMO

The innate immune system represents the first defense line of the host following viral infection. The infection triggers the recognition of pathogen-associated molecular patterns (PAMPs) from the viruses by pattern recognition receptors (PRRs) of the host cell. The interaction between viral PAMPs and PRRs evokes a sophisticated signal transduction system and eventually promotes the expression of type I interferons (IFNs) and proinflammatory cytokines. Ubiquitination plays an indispensable role in fine-tuning almost every single step of this signaling cascade given on its versatile functions. Ubiquitin ligases and deubiquitinases (DUBs), which cooperatively and accurately regulate the dynamic and reversible ubiquitination process, are the master regulators of antiviral signaling. In this review, we concentrate on summarizing the ubiquitin ligases and DUBs that modulate the central signaling molecules in antiviral innate immunity. Especially, we emphasize the ones that were identified by the immunologists from China.


Assuntos
Imunidade Inata , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/imunologia , Ubiquitinação/imunologia , Viroses/imunologia , Animais , Citocinas/metabolismo , Enzimas Desubiquitinantes/metabolismo , Humanos , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais/genética , Receptores Toll-Like/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/genética
19.
EMBO J ; 39(4): e102856, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-31922267

RESUMO

Plant pattern recognition receptors (PRRs) perceive pathogen-associated molecular patterns (PAMPs) to activate immune responses. Medium-chain 3-hydroxy fatty acids (mc-3-OH-FAs), which are widely present in Gram-negative bacteria, were recently shown to be novel PAMPs in Arabidopsis thaliana. The Arabidopsis PRR LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION (LORE) is a G-type lectin receptor-like kinase that recognizes mc-3-OH-FAs and subsequently mounts an immune response; however, the mechanisms underlying LORE activation and downstream signaling are unexplored. Here, we report that one of the mc-3-OH-FAs, 3-OH-C10:0, induces phosphorylation of LORE at tyrosine residue 600 (Y600). Phosphorylated LORE subsequently trans-phosphorylates the receptor-like cytoplasmic kinase PBL34 and its close paralogs, PBL35 and PBL36, and therefore activates plant immunity. Phosphorylation of LORE Y600 is required for downstream phosphorylation of PBL34, PBL35, and PBL36. However, the Pseudomonas syringae effector HopAO1 targets LORE, dephosphorylating the tyrosine-phosphorylated Y600 and therefore suppressing the immune response. These observations uncover the mechanism by which LORE mediates signaling in response to 3-OH-C10:0 in Arabidopsis.


Assuntos
Arabidopsis/imunologia , Doenças das Plantas/imunologia , Imunidade Vegetal/genética , Pseudomonas syringae/imunologia , Arabidopsis/genética , Arabidopsis/microbiologia , Regulação da Expressão Gênica de Plantas , Lectinas/metabolismo , Lipopolissacarídeos/administração & dosagem , Fosforilação , Doenças das Plantas/microbiologia , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais , Tirosina/metabolismo
20.
Insect Biochem Mol Biol ; 118: 103314, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31926881

RESUMO

C-type lectins participate in hemocytic encapsulation as pattern recognition receptors; however, the molecular mechanisms underlying their function remain unknown. In this study, we determined that the encapsulation-promoting function of a C-type lectin, IML-10, may be related to its interaction with hemocytes in the agricultural pest Ostrinia furnacalis. IML-10 possesses two carbohydrate-recognition domains (CRDs) containing EPN and QPD motifs with 4 and 6 conserved cysteine residues, respectively. IML-10 was found to mainly be secreted by the fat body into the larval plasma, and its expression was induced by Sephadex A-25 beads. Anti-IML-10 antibodies inhibited encapsulation-promoting function of IML-10 in the larval plasma. The encapsulation rate of Sephadex A-25 beads decreased from approximately 90%-30% when expression of IML-10 in O. furnacalis larvae was inhibited by RNAi. Moreover, the Sephadex bead-encapsulating ability of hemocytes decreased to almost zero in O. furnacalis larvae with IML-10 knocked out by CRISPR/Cas9, with IML-10 expression clearly decreasing compared to that of the control. Similar to the larval plasma, recombinant IML-10 promoted Sephadex bead encapsulation by hemocytes. Immunohistochemistry analysis showed that IML-10 was able to bind to the surface of both granulocytes and plasmatocytes but not to Sephadex beads as foreign objects. Furthermore, recombinant IML-10 promoted hemocyte aggregation but not adhesion. Therefore, we speculate that IML-10 binds to the surface of hemocytes to promote their aggregation and further improve their encapsulation capacity. These results contribute to clarifying the function of insect C-type lectins in encapsulation.


Assuntos
Hemócitos/metabolismo , Proteínas de Insetos/genética , Lectinas Tipo C/genética , Mariposas/fisiologia , Receptores de Reconhecimento de Padrão/metabolismo , Animais , Proteínas de Insetos/metabolismo , Larva/metabolismo , Lectinas Tipo C/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA