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1.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638802

RESUMO

Chronic hepatitis B virus (HBV) infection remains a major global health problem. The immunopathology of the disease, especially the interplay between HBV and host innate immunity, is poorly understood. Moreover, inconsistent literature on HBV and host innate immunity has led to controversies. However, recently, there has been an increase in the number of studies that have highlighted the link between innate immune responses, including Toll-like receptors (TLRs), and chronic HBV infection. TLRs are the key sensing molecules that detect pathogen-associated molecular patterns and regulate the induction of pro- and anti-inflammatory cytokines, thereby shaping the adaptive immunity. The suppression of TLR response has been reported in patients with chronic hepatitis B (CHB), as well as in other models, including tree shrews, suggesting an association of TLR response in HBV chronicity. Additionally, TLR agonists have been reported to improve the host innate immune response against HBV infection, highlighting the potential of these agonists as immunomodulators for enhancing CHB treatment. In this study, we discuss the current understanding of host innate immune responses during HBV infection, particularly focusing on the TLR response and TLR agonists as immunomodulators.


Assuntos
Hepatite B Crônica/metabolismo , Fatores Imunológicos/farmacologia , Receptores Toll-Like/metabolismo , Animais , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Humanos , Fatores Imunológicos/uso terapêutico , Receptores Toll-Like/agonistas
2.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502105

RESUMO

The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer's disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host's adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible.


Assuntos
Encéfalo/patologia , Viroses do Sistema Nervoso Central/imunologia , Regulação da Expressão Gênica/imunologia , MicroRNAs/metabolismo , Doenças Priônicas/imunologia , Apoptose/genética , Apoptose/imunologia , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/imunologia , Encéfalo/virologia , Viroses do Sistema Nervoso Central/diagnóstico , Viroses do Sistema Nervoso Central/genética , Viroses do Sistema Nervoso Central/virologia , Fator H do Complemento/metabolismo , Citocinas/metabolismo , Humanos , MicroRNAs/análise , MicroRNAs/genética , NF-kappa B/metabolismo , Doenças Priônicas/diagnóstico , Doenças Priônicas/genética , Doenças Priônicas/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo
3.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502383

RESUMO

Chemotherapy-induced intestinal mucositis, a painful debilitating condition affecting up to 40-100% of patients undergoing chemotherapy, can reduce the patients' quality of life, add health care costs and even postpone cancer treatment. In recent years, the relationships between intestinal microbiota dysbiosis and mucositis have drawn much attention in mucositis research. Chemotherapy can shape intestinal microbiota, which, in turn, can aggravate the mucositis through toll-like receptor (TLR) signaling pathways, leading to an increased expression of inflammatory mediators and elevated epithelial cell apoptosis but decreased epithelial cell differentiation and mucosal regeneration. This review summarizes relevant studies related to the relationships of mucositis with chemotherapy regimens, microbiota, TLRs, inflammatory mediators, and intestinal homeostasis, aiming to explore how gut microbiota affects the pathogenesis of mucositis and provides potential new strategies for mucositis alleviation and treatment and development of new therapies.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Tratamento Farmacológico/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Disbiose/microbiologia , Disbiose/fisiopatologia , Fluoruracila/farmacologia , Microbioma Gastrointestinal/fisiologia , Homeostase , Humanos , Intestinos/microbiologia , Microbiota/efeitos dos fármacos , Mucosite/induzido quimicamente , Qualidade de Vida , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/metabolismo , Receptores Toll-Like/fisiologia
4.
Viruses ; 13(9)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34578420

RESUMO

Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as "pDC exhaustion", favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19.


Assuntos
COVID-19/metabolismo , COVID-19/virologia , Interações Hospedeiro-Patógeno , Interferon Tipo I/biossíntese , SARS-CoV-2/fisiologia , Biomarcadores , COVID-19/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/imunologia , Imunomodulação , Receptores Toll-Like/metabolismo
5.
Immunology ; 164(4): 722-736, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34534359

RESUMO

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Linfócitos B/enzimologia , Sistema Imunitário/enzimologia , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , COVID-19/tratamento farmacológico , COVID-19/enzimologia , COVID-19/imunologia , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/enzimologia , Transtornos Linfoproliferativos/imunologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Quimiocinas/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo
6.
Arch Biochem Biophys ; 711: 109029, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34517011

RESUMO

Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.


Assuntos
Anti-Inflamatórios/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Receptores Toll-Like/metabolismo , Trimebutina/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Quimiocinas/metabolismo , Feminino , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7 , Receptor para Produtos Finais de Glicação Avançada/deficiência , Receptor para Produtos Finais de Glicação Avançada/genética , Sepse/induzido quimicamente , Sepse/tratamento farmacológico , Trimebutina/uso terapêutico
7.
Cells ; 10(9)2021 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-34572113

RESUMO

The increased level of hydrogen peroxide accompanies some modes of macrophage specification and is linked to ROS-based antimicrobial activity of these phagocytes. In this study, we show that activation of toll-like receptors with bacterial components such as LPS is accompanied by the decline in transcription of hydrogen peroxide decomposing enzyme-catalase, suppression of which facilitates the polarization of human macrophages towards the pro-inflammatory phenotype. The chromatin remodeling at the CAT promoter involves LSD1 and HDAC1, but activity of the first enzyme defines abundance of the two proteins on chromatin, histone acetylation status and the CAT transcription. LSD1 inhibition prior to macrophage activation with LPS prevents CAT repression by enhancing the LSD1 and interfering with the HDAC1 recruitment to the gene promoter. The maintenance of catalase level with LSD1 inhibitors during M1 polarization considerably limits LPS-triggered expression of some pro-inflammatory cytokines and markers such as IL1ß, TNFα, COX2, CD14, TLR2, and IFNAR, but the effect of LSD1 inhibitors is lost upon catalase deficiency. Summarizing, activity of LSD1 allows for the CAT repression in LPS stimulated macrophages, which negatively controls expression of some key pro-inflammatory markers. LSD1 inhibitors can be considered as possible immunosuppressive drugs capable of limiting macrophage M1 specialization.


Assuntos
Catalase/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Histona Desmetilases/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Receptores Toll-Like/metabolismo , Catalase/genética , Catalase/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Histona Desacetilase 1/genética , Histona Desmetilases/genética , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Transdução de Sinais , Receptores Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Mol Sci ; 22(18)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34576280

RESUMO

Avoiding excessive or insufficient immune responses and maintaining homeostasis are critical for animal survival. Although many positive or negative modulators involved in immune responses have been identified, little has been reported to date concerning whether the long non-coding RNA (lncRNA) can regulate Drosophila immunity response. In this study, we firstly discover that the overexpression of lncRNA-CR11538 can inhibit the expressions of antimicrobial peptides Drosomycin (Drs) and Metchnikowin (Mtk) in vivo, thereby suppressing the Toll signaling pathway. Secondly, our results demonstrate that lncRNA-CR11538 can interact with transcription factors Dif/Dorsal in the nucleus based on both subcellular localization and RIP analyses. Thirdly, our findings reveal that lncRNA-CR11538 can decoy Dif/Dorsal away from the promoters of Drs and Mtk to repress their transcriptions by ChIP-qPCR and dual luciferase report experiments. Fourthly, the dynamic expression changes of Drs, Dif, Dorsal and lncRNA-CR11538 in wild-type flies (w1118) at different time points after M. luteus stimulation disclose that lncRNA-CR11538 can help Drosophila restore immune homeostasis in the later period of immune response. Overall, our study reveals a novel mechanism by which lncRNA-CR11538 serves as a Dif/Dorsal decoy to downregulate antimicrobial peptide expressions for restoring Drosophila Toll immunity homeostasis, and provides a new insight into further studying the complex regulatory mechanism of animal innate immunity.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/imunologia , Drosophila melanogaster/metabolismo , Micrococcus luteus , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Proteínas Citotóxicas Formadoras de Poros/farmacologia , RNA Longo não Codificante , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/microbiologia , Homeostase , Imunidade Inata , Masculino , NF-kappa B/metabolismo , Proteínas Nucleares/genética , Fosfoproteínas/genética , Regiões Promotoras Genéticas , RNA-Seq , Sepse , Transdução de Sinais , Frações Subcelulares , Receptores Toll-Like/metabolismo , Fatores de Transcrição/genética
9.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360632

RESUMO

Otitis media is mainly caused by upper respiratory tract infection and eustachian tube dysfunction. If external upper respiratory tract infection is not detected early in the middle ear, or an appropriate immune response does not occur, otitis media can become a chronic state or complications may occur. Therefore, given the important role of Toll-like receptors (TLRs) in the early response to external antigens, we surveyed the role of TLRs in otitis media. To summarize the role of TLR in otitis media, we reviewed articles on the expression of TLRs in acute otitis media (AOM), otitis media with effusion (OME), chronic otitis media (COM) with cholesteatoma, and COM without cholesteatoma. Many studies showed that TLRs 1-10 are expressed in AOM, OME, COM with cholesteatoma, and COM without cholesteatoma. TLR expression in the normal middle ear mucosa is absent or weak, but is increased in inflammatory fluid of AOM, effusion of OME, and granulation tissue and cholesteatoma of COM. In addition, TLRs show increased or decreased expression depending on the presence or absence of bacteria, recurrence of disease, tissue type, and repeated surgery. In conclusion, expression of TLRs is associated with otitis media. Inappropriate TLR expression, or delayed or absent induction, are associated with the occurrence, recurrence, chronicization, and complications of otitis media. Therefore, TLRs are very important in otitis media and closely related to its etiology.


Assuntos
Otite Média/metabolismo , Receptores Toll-Like/metabolismo , Animais , Humanos
10.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360659

RESUMO

Platelets are hematopoietic cells whose main function has for a long time been considered to be the maintenance of vascular integrity. They have an essential role in the hemostatic response, but they also have functional capabilities that go far beyond it. This review will provide an overview of platelet functions. Indeed, stress signals may induce platelet apoptosis through proapoptotis or hemostasis receptors, necrosis, and even autophagy. Platelets also interact with immune cells and modulate immune responses in terms of activation, maturation, recruitment and cytokine secretion. This review will also show that platelets, thanks to their wide range of innate immune receptors, and in particular toll-like receptors, and can be considered sentinels actively participating in the immuno-surveillance of the body. We will discuss the diversity of platelet responses following the engagement of these receptors as well as the signaling pathways involved. Finally, we will show that while platelets contribute significantly, via their TLRs, to immune response and inflammation, these receptors also participate in the pathophysiological processes associated with various pathogens and diseases, including cancer and atherosclerosis.


Assuntos
Aterosclerose/patologia , Plaquetas/patologia , Imunidade Inata/imunologia , Neoplasias/patologia , Ativação Plaquetária , Receptores Imunológicos/metabolismo , Receptores Toll-Like/metabolismo , Animais , Aterosclerose/imunologia , Aterosclerose/metabolismo , Plaquetas/imunologia , Plaquetas/metabolismo , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo
11.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360824

RESUMO

Different mechanisms were proposed as responsible for COVID-19 neurological symptoms but a clear one has not been established yet. In this work we aimed to study SARS-CoV-2 capacity to infect pediatric human cortical neuronal HCN-2 cells, studying the changes in the transcriptomic profile by next generation sequencing. SARS-CoV-2 was able to replicate in HCN-2 cells, that did not express ACE2, confirmed also with Western blot, and TMPRSS2. Looking for pattern recognition receptor expression, we found the deregulation of scavenger receptors, such as SR-B1, and the downregulation of genes encoding for Nod-like receptors. On the other hand, TLR1, TLR4 and TLR6 encoding for Toll-like receptors (TLRs) were upregulated. We also found the upregulation of genes encoding for ERK, JNK, NF-κB and Caspase 8 in our transcriptomic analysis. Regarding the expression of known receptors for viral RNA, only RIG-1 showed an increased expression; downstream RIG-1, the genes encoding for TRAF3, IKKε and IRF3 were downregulated. We also found the upregulation of genes encoding for chemokines and accordingly we found an increase in cytokine/chemokine levels in the medium. According to our results, it is possible to speculate that additionally to ACE2 and TMPRSS2, also other receptors may interact with SARS-CoV-2 proteins and mediate its entry or pathogenesis in pediatric cortical neurons infected with SARS-CoV-2. In particular, TLRs signaling could be crucial for the neurological involvement related to SARS-CoV-2 infection.


Assuntos
COVID-19/metabolismo , Córtex Cerebral/metabolismo , Neurônios/virologia , SARS-CoV-2/patogenicidade , Receptores Toll-Like/metabolismo , COVID-19/genética , COVID-19/imunologia , Criança , Citocinas/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Neurônios/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Transdução de Sinais/genética , Receptores Toll-Like/genética , Replicação Viral
12.
Chem Commun (Camb) ; 57(68): 8421-8424, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34373867

RESUMO

Combining the stability of the N-heterocyclic carbenes (NHCs) and broad-spectrum recognition of toll-like receptor (TLR) proteins, we report new electrochemical biosensors for bacteria detection. Instead of traditional thiol-gold chemistry, newly synthesized NHCs are employed as the linker molecules to immobilize TLR bio-recognition elements on gold electrodes. Our proof-of-concept methodology includes testing the fidelity of TLR-based electrochemical sensors with NHC linkers. The performance of the biosensors is demonstrated using whole-cell bacterial cultures.


Assuntos
Técnicas Eletroquímicas , Compostos Heterocíclicos/síntese química , Receptores Toll-Like/química , Técnicas Biossensoriais/métodos , Eletrodos , Escherichia coli , Ouro , Compostos Heterocíclicos/química , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Receptores Toll-Like/metabolismo
13.
J Med Virol ; 93(11): 6116-6123, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34375002

RESUMO

Virus invasion activates the host's innate immune response, inducing the production of numerous cytokines and interferons to eliminate pathogens. Except for viral DNA/RNA, viral proteins are also targets of pattern recognition receptors. Membrane-bound receptors such as Toll-like receptor (TLR)1, TLR2, TLR4, TLR6, and TLR10 relate to the recognition of viral proteins. Distinct TLRs perform both protective and detrimental roles for a specific virus. Here, we review viral proteins serving as pathogen-associated molecular patterns and their corresponding TLRs. These viruses are all enveloped, including respiratory syncytial virus, hepatitis C virus, measles virus, herpesvirus human immunodeficiency virus, and coronavirus, and can encode proteins to activate innate immunity in a TLR-dependent way. The TLR-viral protein relationship plays an important role in innate immunity activation. A detailed understanding of their pathways contributes to a novel direction for vaccine development.


Assuntos
Imunidade Inata , Padrões Moleculares Associados a Patógenos/metabolismo , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Proteínas Virais/metabolismo , Viroses/imunologia , Vírus/imunologia , Animais , HIV/imunologia , HIV/metabolismo , HIV/patogenicidade , Hepacivirus/imunologia , Hepacivirus/metabolismo , Hepacivirus/patogenicidade , Herpesviridae/imunologia , Herpesviridae/metabolismo , Herpesviridae/patogenicidade , Humanos , Vírus do Sarampo/imunologia , Vírus do Sarampo/metabolismo , Vírus do Sarampo/patogenicidade , Padrões Moleculares Associados a Patógenos/química , Vírus Sinciciais Respiratórios/imunologia , Vírus Sinciciais Respiratórios/metabolismo , Vírus Sinciciais Respiratórios/patogenicidade , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Proteínas Virais/química , Viroses/virologia , Vírus/metabolismo , Vírus/patogenicidade
14.
J Immunol ; 207(5): 1448-1455, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34362834

RESUMO

Identification of the receptors involved in innate immune recognition of Staphylococcus aureus, a major cause of morbidity and mortality in humans, is essential to develop alternative strategies to treat infections caused by antibiotic-resistant strains. In the current study, we examine the role of endosomal TLRs, which sense the presence of prokaryotic-type nucleic acids, in anti-staphylococcal host defenses using infection models involving genetically defective mice. Single deficiencies in TLR7, 9, or 13 resulted in mild or no decrease in host defenses. However, the simultaneous absence of TLR7, 9, and 13 resulted in markedly increased susceptibility to cutaneous and systemic S. aureus infection concomitantly with decreased production of proinflammatory chemokines and cytokines, neutrophil recruitment to infection sites, and reduced production of reactive oxygen species. This phenotype was significantly more severe than that of mice lacking TLR2, which senses the presence of staphylococcal lipoproteins. Notably, the combined absence of TLR7, 9, and 13 resulted in complete abrogation of IL-12 p70 and IFN-ß responses to staphylococcal stimulation in macrophages. Taken together, our data highlight the presence of a highly integrated endosomal detection system, whereby TLR7, 9, and 13 cooperate in sensing the presence of staphylococcal nucleic acids. We demonstrate that the combined absence of these receptors cannot be compensated for by cell surface-associated TLRs, such as TLR2, or cytosolic receptors. These data may be useful to devise strategies aimed at stimulating innate immune receptors to treat S. aureus infections.


Assuntos
Endossomos/metabolismo , Glicoproteínas de Membrana/metabolismo , Neutrófilos/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Humanos , Imunidade Inata , Mediadores da Inflamação/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 7 Toll-Like/genética , Receptor Toll-Like 9/genética , Receptores Toll-Like/genética
15.
Nutrients ; 13(8)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34444741

RESUMO

Gut microbiota has emerged as a major metabolically active organ with critical functions in both health and disease. The trillions of microorganisms hosted by the gastrointestinal tract are involved in numerous physiological and metabolic processes including modulation of appetite and regulation of energy in the host spanning from periphery to the brain. Indeed, bacteria and their metabolic byproducts are working in concert with the host chemosensory signaling pathways to affect both short- and long-term ingestive behavior. Sensing of nutrients and taste by specialized G protein-coupled receptor cells is important in transmitting food-related signals, optimizing nutrition as well as in prevention and treatment of several diseases, notably obesity, diabetes and associated metabolic disorders. Further, bacteria metabolites interact with specialized receptors cells expressed by gut epithelium leading to taste and appetite response changes to nutrients. This review describes recent advances on the role of gut bacteria in taste perception and functions. It further discusses how intestinal dysbiosis characteristic of several pathological conditions may alter and modulate taste preference and food consumption via changes in taste receptor expression.


Assuntos
Fenômenos Fisiológicos Bacterianos , Microbioma Gastrointestinal/fisiologia , Intestinos/microbiologia , Percepção Gustatória , Animais , Antineoplásicos/uso terapêutico , Cirurgia Bariátrica , COVID-19/fisiopatologia , Dieta , Disbiose/fisiopatologia , Comportamento Alimentar , Hormônios/metabolismo , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Receptores Acoplados a Proteínas G/metabolismo , Paladar , Papilas Gustativas/fisiologia , Receptores Toll-Like/metabolismo
16.
Curr Issues Mol Biol ; 43(2): 818-830, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34449561

RESUMO

BACKGROUND: A high-cholesterol diet (HCD) induces vascular atherosclerosis through vascular inflammatory and immunological processes via TLRs. The aim of this study is to investigate the mRNA expression of TLRs and other noxious biomarkers expressing inflammation, fibrosis, apoptosis, and cardiac dysfunction in the rabbit myocardium during (a) high-cholesterol diet (HCD), (b) normal diet resumption and (c) fluvastatin or rosuvastatin treatment. METHODS: Forty-eight male rabbits were randomly divided into eight groups (n = 6/group). In the first experiment, three groups were fed with HCD for 1, 2 and 3 months. In the second experiment, three groups were fed with HCD for 3 months, followed by normal chow for 1 month and administration of fluvastatin or rosuvastatin for 1 month. Control groups were fed with normal chow for 90 and 120 days. The whole myocardium was removed; total RNA was isolated from acquired samples, and polymerase chain reaction, reverse transcription PCR and quantitative real-time PCR were performed. RESULTS: mRNA of TLRs 2, 3, 4 and 8; interleukin-6; TNF-a; metalloproteinase-2; tissue inhibitor of metalloproteinase-1; tumor protein 53; cysteinyl aspartate specific proteinase-3; and brain natriuretic peptide (BNP) increased in HCD. Statins but not resumption of a normal diet decreased levels of these biomarkers and increased levels of antifibrotic factors. CONCLUSIONS: HCD increases the levels of TLRs; inflammatory, fibrotic and apoptotic factors; and BNP in the rabbit myocardium. Atherogenic diets adversely affect the myocardium at a molecular level and are reversed by statins.


Assuntos
Colesterol na Dieta/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/tratamento farmacológico , Miocárdio/metabolismo , Receptores Toll-Like/metabolismo , Animais , Modelos Animais de Doenças , Fluvastatina/farmacologia , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Masculino , Miocárdio/patologia , Coelhos , Rosuvastatina Cálcica/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
17.
Front Immunol ; 12: 686846, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408745

RESUMO

Chitooligosaccharide (COS) is an important immune enhancer and has been proven to have a variety of biological activities. Our previous research has established an M1 polarization mode by COS in blunt snout bream (Megalobrama amblycephala) macrophages, but the mechanism of COS activation of blunt snout bream macrophages remains unclear. In this study, we further explored the internalization mechanism and signal transduction pathway of chitooligosaccharide hexamer (COS6) in blunt snout bream macrophages. The results showed that mannose receptor C-type lectin-like domain 4-8 of M. amblycephala (MaMR CTLD4-8) could recognize and bind to COS6 and mediate COS6 into macrophages by both clathrin-dependent and caveolin-dependent pathways. In the inflammatory response of macrophages activated by COS6, the gene expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and nitric oxide synthase 2 (NOS2) was significantly inhibited after MaMR CTLD4-8-specific antibody blockade. However, even if it was blocked, the expression of these inflammation-related genes was still relatively upregulated, which suggested that there are other receptors involved in immune regulation. Further studies indicated that MaMR CTLD4-8 and Toll-like receptor 4 (TLR4) cooperated to regulate the pro-inflammatory response of macrophages caused by COS6. Taken together, these results revealed that mannose receptor (MR) CTLD4-8 is indispensable in the process of recognition, binding, internalization, and immunoregulation of COS in macrophages of blunt snout bream.


Assuntos
Quitosana/metabolismo , Cyprinidae/imunologia , Expressão Gênica , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Lectinas de Ligação a Manose/metabolismo , Oligossacarídeos/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Anticorpos/efeitos adversos , Cyprinidae/metabolismo , Interleucina-1beta/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Receptores Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Cells ; 10(8)2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34440800

RESUMO

The innate immune system plays a critical role in the early detection of pathogens, primarily by relying on pattern-recognition receptor (PRR) signaling molecules. Nucleotide-binding oligomerization domain 2 (NOD2) is a cytoplasmic receptor that recognizes invading molecules and danger signals inside the cells. Recent studies highlight the importance of NOD2's function in maintaining the homeostasis of human body microbiota and innate immune responses, including induction of proinflammatory cytokines, regulation of autophagy, modulation of endoplasmic reticulum (ER) stress, etc. In addition, there is extensive cross-talk between NOD2 and the Toll-like receptors that are so important in the induction and tuning of adaptive immunity. Polymorphisms of NOD2's encoding gene are associated with several pathological conditions, highlighting NOD2's functional importance. In this study, we summarize NOD2's role in cellular signaling pathways and take a look at the possible consequences of common NOD2 polymorphisms on the structure and function of this receptor.


Assuntos
Autofagia/genética , Estresse do Retículo Endoplasmático/genética , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo Genético , Transdução de Sinais/genética , Imunidade Adaptativa/genética , Humanos , Imunidade Inata/genética , Proteína Adaptadora de Sinalização NOD2/química , Proteína Adaptadora de Sinalização NOD2/metabolismo , Domínios Proteicos , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
19.
BMC Genomics ; 22(1): 562, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34289811

RESUMO

BACKGROUND: Arthropoda, the most numerous and diverse metazoan phylum, has species in many habitats where they encounter various microorganisms and, as a result, mechanisms for pathogen recognition and elimination have evolved. The Toll pathway, involved in the innate immune system, was first described as part of the developmental pathway for dorsal-ventral differentiation in Drosophila. Its later discovery in vertebrates suggested that this system was extremely conserved. However, there is variation in presence/absence, copy number and sequence divergence in various genes along the pathway. As most studies have only focused on Diptera, for a comprehensive and accurate homology-based approach it is important to understand gene function in a number of different species and, in a group as diverse as insects, the use of species belonging to different taxonomic groups is essential. RESULTS: We evaluated the diversity of Toll pathway gene families in 39 Arthropod genomes, encompassing 13 different Insect Orders. Through computational methods, we shed some light into the evolution and functional annotation of protein families involved in the Toll pathway innate immune response. Our data indicates that: 1) intracellular proteins of the Toll pathway show mostly species-specific expansions; 2) the different Toll subfamilies seem to have distinct evolutionary backgrounds; 3) patterns of gene expansion observed in the Toll phylogenetic tree indicate that homology based methods of functional inference might not be accurate for some subfamilies; 4) Spatzle subfamilies are highly divergent and also pose a problem for homology based inference; 5) Spatzle subfamilies should not be analyzed together in the same phylogenetic framework; 6) network analyses seem to be a good first step in inferring functional groups in these cases. We specifically show that understanding Drosophila's Toll functions might not indicate the same function in other species. CONCLUSIONS: Our results show the importance of using species representing the different orders to better understand insect gene content, origin and evolution. More specifically, in intracellular Toll pathway gene families the presence of orthologues has important implications for homology based functional inference. Also, the different evolutionary backgrounds of Toll gene subfamilies should be taken into consideration when functional studies are performed, especially for TOLL9, TOLL, TOLL2_7, and the new TOLL10 clade. The presence of Diptera specific clades or the ones lacking Diptera species show the importance of overcoming the Diptera bias when performing functional characterization of Toll pathways.


Assuntos
Fator 88 de Diferenciação Mieloide , Receptores Toll-Like , Animais , Evolução Molecular , Fator 88 de Diferenciação Mieloide/genética , Filogenia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
20.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201613

RESUMO

Disruptions in the intestinal epithelial barrier can result in devastating consequences and a multitude of disease syndromes, particularly among preterm neonates. The association between barrier dysfunction and intestinal dysbiosis suggests that the intestinal barrier function is interactive with specific gut commensals and pathogenic microbes. In vitro and in vivo studies demonstrate that probiotic supplementation promotes significant upregulation and relocalization of interepithelial tight junction proteins, which form the microscopic scaffolds of the intestinal barrier. Probiotics facilitate some of these effects through the ligand-mediated stimulation of several toll-like receptors that are expressed by the intestinal epithelium. In particular, bacterial-mediated stimulation of toll-like receptor-2 modulates the expression and localization of specific protein constituents of intestinal tight junctions. Given that ingested prebiotics are robust modulators of the intestinal microbiota, prebiotic supplementation has been similarly investigated as a potential, indirect mechanism of barrier preservation. Emerging evidence suggests that prebiotics may additionally exert a direct effect on intestinal barrier function through mechanisms independent of the gut microbiota. In this review, we summarize current views on the effects of pro- and prebiotics on the intestinal epithelial barrier as well as on non-epithelial cell barrier constituents, such as the enteric glial cell network. Through continued investigation of these bioactive compounds, we can maximize their therapeutic potential for preventing and treating gastrointestinal diseases associated with impaired intestinal barrier function and dysbiosis.


Assuntos
Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/fisiologia , Prebióticos , Probióticos/farmacologia , Junções Íntimas/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Lactente , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Receptores Toll-Like/metabolismo
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