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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.
J Hematol Oncol ; 14(1): 176, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34715891

RESUMO

Glioma represents a fast proliferating and highly invasive brain tumor which is resistant to current therapies and invariably recurs. Despite some advancements in anti-glioma therapies, patients' prognosis remains poor. Toll-like receptors (TLRs) act as the first line of defense in the immune system being the detectors of those associated with bacteria, viruses, and danger signals. In the glioma microenvironment, TLRs are expressed on both immune and tumor cells, playing dual roles eliciting antitumoral (innate and adaptive immunity) and protumoral (cell proliferation, migration, invasion, and glioma stem cell maintenance) responses. Up to date, several TLR-targeting therapies have been developed aiming at glioma bulk and stem cells, infiltrating immune cells, the immune checkpoint axis, among others. While some TLR agonists exhibited survival benefit in clinical trials, it attracts more attention when they are involved in combinatorial treatment with radiation, chemotherapy, immune vaccination, and immune checkpoint inhibition in glioma treatment. TLR agonists can be used as immune modulators to enhance the efficacy of other treatment, to avoid dose accumulation, and what brings more interests is that they can potentiate immune checkpoint delayed resistance to PD-1/PD-L1 blockade by upregulating PD-1/PD-L1 overexpression, thus unleash powerful antitumor responses when combined with immune checkpoint inhibitors. Herein, we focus on recent developments and clinical trials exploring TLR-based treatment to provide a picture of the relationship between TLR and glioma and their implications for immunotherapy.


Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Receptores Toll-Like/imunologia , Animais , Neoplasias Encefálicas/imunologia , Glioma/imunologia , Humanos , Modelos Moleculares , Receptores Toll-Like/agonistas
3.
J Med Chem ; 64(12): 8010-8041, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34107682

RESUMO

Toll-like receptors (TLRs) are members of a large family of evolutionarily conserved pattern recognition receptors (PRRs), which serve as key components of the innate immune system by playing a pivotal role in sensing "nonself" ligands. Endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) can recognize pathogen-derived nucleic acid and initiate an innate immune response because they react against both self- and non-self-origin nucleic acid molecules. Accordingly, both receptor agonists and antagonists are potentially useful in disparate clinical contexts and thus are globally sought after. Recent research has revealed that agonists and antagonists share an overlapping binding region. This Perspective highlights rational medicinal chemistry approaches to elucidate the structural attributes of small molecules capable of agonism or antagonism or of elegantly switching between the two. The structural evolution of different chemotypes can provide the framework for the future development of endosomal TLR agonists and antagonists.


Assuntos
Compostos Heterocíclicos/química , Receptores Toll-Like/agonistas , Receptores Toll-Like/antagonistas & inibidores , Animais , Endossomos/química , Células HEK293 , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/farmacologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Receptores Toll-Like/metabolismo
5.
ACS Appl Mater Interfaces ; 13(21): 24442-24452, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34008947

RESUMO

Most cancers contain abundant tumor-associated macrophages (TAMs). TAMs usually display a tumor-supportive M2-like phenotype; they promote tumor growth and influence lymphocyte infiltration, leading to immunosuppression. These properties have made TAMs an attractive cancer immunotherapy target. One promising immunotherapeutic strategy involves switching the tumor-promoting immune suppressive microenvironment by reprogramming TAMs. However, clinical trials of M2-like macrophage reprogramming have yielded unsatisfactory results due to their low efficacy and nonselective effects. In this article, we describe the development of M2-like macrophage-targeting nanoparticles (PNP@R@M-T) that efficiently and selectively deliver drugs to 58% of M2-like macrophages, over 39% of M1-like macrophages, and 32% of dendritic cells within 24 h in vivo. Compared with the control groups, administration of PNP@R@M-T dramatically reprogrammed the M2-like macrophages (51%), reduced tumor size (82%), and prolonged survival. Our findings indicate that PNP@R@M-T nanoparticles provide an effective and selective reprogramming strategy for macrophage-mediated cancer immunotherapy.


Assuntos
Imunoterapia/métodos , Nanopartículas , Medicina de Precisão , Receptores Toll-Like/agonistas , Macrófagos Associados a Tumor/imunologia , Animais , Humanos , Camundongos
6.
Cell Immunol ; 365: 104364, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33932876

RESUMO

Ulcerative colitis (UC) represents a relapsing and inflammatory bowel disease which is commonly linked with the communications between dysfunction of epithelium and mucosal immune responses. Though caffeic acid (CA) has numerous pharmacological capacities, whether CA demonstrates immunoregulation on the mucosal immune responses remains ill-defined. Herein, the present research demonstrated that CA could dramatically attenuate the mucosal inflammation, as evidenced by improving the disease severity, serum biochemical indexes, mucosal ulcerations, loss of epithelium and crypts, and secretion of inflammatory cytokines in the colonic homogenates and explants culture. Consistently, CA could interfere with the infiltration and function of mononuclear macrophages in the mucosa, MLNs, and spleens of UC. Furthermore, CA exerted direct suppressive effects on the activation of BMDMs upon the exposure of TLRs agonists in vitro. Taken together, CA could attenuate DSS-induced murine UC through interfering with the activation of macrophages, which might provide an alternative therapeutic option for UC.


Assuntos
Ácidos Cafeicos/metabolismo , Colite/imunologia , Doenças Inflamatórias Intestinais/imunologia , Macrófagos/imunologia , Receptores Toll-Like/metabolismo , Animais , Ácidos Cafeicos/imunologia , Células Cultivadas , Colite/terapia , Sulfato de Dextrana , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/terapia , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Toll-Like/agonistas
7.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925089

RESUMO

Deeply understanding the virus-host interaction is a prerequisite for developing effective anti-viral strategies. Traditionally, the transporter associated with antigen processing type 1 (TAP1) is critical for antigen presentation to regulate adaptive immunity. However, its role in controlling viral infections through modulating innate immune signaling is not yet fully understood. In the present study, we reported that TAP1, as a product of interferon-stimulated genes (ISGs), had broadly antiviral activity against various viruses such as herpes simplex virus 1 (HSV-1), adenoviruses (AdV), vesicular stomatitis virus (VSV), dengue virus (DENV), Zika virus (ZIKV), and influenza virus (PR8) etc. This antiviral activity by TAP1 was further confirmed by series of loss-of-function and gain-of-function experiments. Our further investigation revealed that TAP1 significantly promoted the interferon (IFN)-ß production through activating the TANK binding kinase-1 (TBK1) and the interferon regulatory factor 3 (IRF3) signaling transduction. Our work highlighted the broadly anti-viral function of TAP1 by modulating innate immunity, which is independent of its well-known function of antigen presentation. This study will provide insights into developing novel vaccination and immunotherapy strategies against emerging infectious diseases.


Assuntos
Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/imunologia , Antivirais/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Interferon Tipo I/biossíntese , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/imunologia , Camundongos , Modelos Imunológicos , Proteínas Serina-Treonina Quinases/imunologia , Células RAW 264.7 , Receptores Toll-Like/agonistas , Viroses/imunologia
8.
Front Immunol ; 12: 624197, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815376

RESUMO

Vaccines have played a pivotal role in improving public health, however, many infectious diseases lack an effective vaccine. Controlling the spread of infectious diseases requires continuing studies to develop new and improved vaccines. Our laboratory has been investigating the immune enhancing mechanisms of Toll-like receptor (TLR) ligand-based adjuvants, including the TLR2 ligand Neisseria meningitidis outer membrane protein, PorB. Adjuvant use of PorB increases costimulatory factors on antigen presenting cells (APC), increases antigen specific antibody production, and cytokine producing T cells. We have demonstrated that macrophage expression of MyD88 (required for TLR2 signaling) is an absolute requirement for the improved antibody response induced by PorB. Here-in, we specifically investigated the role of subcapsular CD169+ marginal zone macrophages in antibody production induced by the use of TLR-ligand based adjuvants (PorB and CpG) and non-TLR-ligand adjuvants (aluminum salts). CD169 knockout mice and mice treated with low dose clodronate treated animals (which only remove marginal zone macrophages), were used to investigate the role of these macrophages in adjuvant-dependent antibody production. In both sets of mice, total antigen specific immunoglobulins (IgGs) were diminished regardless of adjuvant used. However, the greatest reduction was seen with the use of TLR ligands as adjuvants. In addition, the effect of the absence of CD169+ macrophages on adjuvant induced antigen and antigen presenting cell trafficking to the lymph nodes was examined using immunofluorescence by determining the relative extent of antigen loading on dendritic cells (DCs) and antigen deposition on follicular dendritic cells (FDC). Interestingly, only vaccine preparations containing PorB had significant decreases in antigen deposition in lymphoid follicles and germinal centers in CD169 knockout mice or mice treated with low dose clodronate as compared to wildtype controls. Mice immunized with CpG containing preparations demonstrated decreased FDC networks in the mice treated with low dose clodronate. Conversely, alum containing preparations only demonstrated significant decreases in IgG in CD169 knockout mice. These studies stress that importance of subcapsular macrophages and their unique role in adjuvant-mediated antibody production, potentially due to an effect of these adjuvants on antigen trafficking to the lymph node and deposition on follicular dendritic cells.


Assuntos
Adjuvantes Imunológicos/farmacologia , Compostos de Alúmen/farmacologia , Imunogenicidade da Vacina , Macrófagos/efeitos dos fármacos , Oligodesoxirribonucleotídeos/farmacologia , Ovalbumina/farmacologia , Porinas/farmacologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Receptores Toll-Like/agonistas , Animais , Ácido Clodrônico/farmacologia , Células Dendríticas Foliculares/efeitos dos fármacos , Células Dendríticas Foliculares/imunologia , Células Dendríticas Foliculares/metabolismo , Imunoglobulina G/sangue , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oligodesoxirribonucleotídeos/imunologia , Ovalbumina/imunologia , Porinas/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Transdução de Sinais , Receptores Toll-Like/metabolismo , Vacinação
9.
Nat Commun ; 12(1): 1836, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758175

RESUMO

To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.


Assuntos
Bactérias/imunologia , Células Epiteliais/imunologia , Imunidade Inata , Lipopeptídeos/imunologia , NF-kappa B/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Bactérias/metabolismo , Linhagem Celular , Citocinas/metabolismo , Citocinas/farmacologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Flagelina/farmacologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Processamento de Imagem Assistida por Computador , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Hibridização in Situ Fluorescente , Glândulas Mamárias Animais , Camundongos , Organoides/efeitos dos fármacos , Organoides/imunologia , Organoides/metabolismo , Regiões Promotoras Genéticas , RNA-Seq , Transdução de Sinais/imunologia , Análise de Célula Única , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/genética , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo
10.
Biosci Trends ; 15(2): 74-82, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33716257

RESUMO

Alcoholism is a global socially significant problem and still remains one of the leading causes of disability and premature death. One of the main signs of the disease is the loss of cognitive control over the amount of alcohol consumed. Among the mechanisms of the development of this pathology, changes in neuroimmune mechanisms occurring in the brain during prolonged alcohol consumption and its withdrawal have recently become the focus of numerous studies. Ethanol consumption leads to the activation of neuroimmune signaling in the central nervous system through many subtypes of Toll-like receptors (TLRs), as well as release of their endogenous agonists (high-mobility group protein B1 (HMGB1), S100 protein, heat shock proteins (HSPs), and extracellular matrix degradation proteins). TLR activation triggers intracellular molecular cascades of reactions leading to increased expression of genes of the innate immune system, particularly, proinflammatory cytokines, causing further development of a persistent neuroinflammatory process in the central nervous system. This leads to death of neurons and neuroglial cells in various brain structures, primarily in those associated with the development of a pathological craving for alcohol. In addition, there is evidence that some subtypes of TLRs (TLR3, TLR4) are able to form heterodimers with neuropeptide receptors, thereby possibly playing other roles in the central nervous system, in addition to participating in the activation of the innate immune system.


Assuntos
Alcoolismo/imunologia , Fissura , Etanol/efeitos adversos , Neuroimunomodulação/efeitos dos fármacos , Receptores Toll-Like/metabolismo , Alcoolismo/metabolismo , Alcoolismo/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Etanol/administração & dosagem , Humanos , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Transdução de Sinais/imunologia , Receptores Toll-Like/agonistas
11.
J Exp Med ; 218(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33616624

RESUMO

Frequent outbreaks of viruses have caused a serious threat to public health. Previous evidence has revealed that DNA methylation is correlated with viral infections, but its role in innate immunity remains poorly investigated. Additionally, DNA methylation inhibitors promote IFN-I by upregulating endogenous retrovirus; however, studies of intrinsically demethylated tumors do not support this conclusion. This study found that Uhrf1 deficiency in myeloid cells significantly upregulated Ifnb expression, increasing resistance to viral infection. We performed whole-genome bisulfite sequencing and found that a single-nucleotide methylation site in the Ifnb promoter region disrupted IRF3 recruitment. We used site-specific mutant knock-in mice and a region-specific demethylation tool to confirm that this methylated site plays a critical role in regulating Ifnb expression and antiviral responses. These findings provide essential insight into DNA methylation in the regulation of the innate antiviral immune response.


Assuntos
Antivirais/metabolismo , Metilação de DNA/genética , Imunidade Inata/genética , Interferon Tipo I/metabolismo , Nucleotídeos/genética , Animais , Sequência de Bases , Proteínas Estimuladoras de Ligação a CCAAT/deficiência , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Cromatina/metabolismo , Ilhas de CpG/genética , Citocinas/metabolismo , Células HEK293 , Homeostase , Humanos , Sistema Imunitário/metabolismo , Vacinas contra Influenza/imunologia , Camundongos , Células Mieloides/metabolismo , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Regiões Promotoras Genéticas/genética , Transdução de Sinais , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Transcrição Genética , Transcriptoma/genética , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/metabolismo
12.
ACS Chem Biol ; 16(2): 380-388, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33523635

RESUMO

We report a mechanistic study comparing the immune activation of conjugated Toll-like receptor (TLR) agonists and their unlinked mixtures. Herein, we synthesized a set of six linked dual agonists with different ligands, molecular structures, receptor locations, and biophysical characteristics. With these dimers, we ran a series of in vitro cell-based assays, comparing initial and overall NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation, cytokine expression profiles, as well as time-resolved TNF-α (Tumor Necrosis Factor alpha) expression. We show that initial activation kinetics, ligand specificity, and the dose of the agonist influence the activity of these linked TLR systems. These results can help improve vaccine design by showing how linked TLR agonists can improve their potency with the appropriate selection of key criteria.


Assuntos
Compostos Heterocíclicos com 3 Anéis/farmacologia , Lipopeptídeos/farmacologia , Oligonucleotídeos/farmacologia , Receptores Toll-Like/agonistas , Animais , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 3 Anéis/síntese química , Cinética , Ligantes , Lipopeptídeos/síntese química , Camundongos , NF-kappa B/metabolismo , Oligonucleotídeos/síntese química , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
13.
Biomed Pharmacother ; 137: 111276, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33485119

RESUMO

Appropriate activation of macrophages is critical for the elimination of Leishmania parasites, which resides in this cell. Some species of Leishmania (L.) fails to stimulate macrophages and establish a chronic infection. To overcome this suppression and induce an innate immune response, the effect of PLGA-encapsulated soluble antigens of Leishmania (SLA) along with agonists of TLR1/2 (Pam3CSK4) and TLR7/8 (R848) nanoparticles (NPs) on activation of L. major-infected-macrophages were investigated and were compared with those of soluble formulations. SLA and R848 were encapsulated into the PLGA, while Pam3CSK4 adsorbed onto the surface of nanoparticles. The kinetics of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and iNOS genes expression were investigated by qPCR over 72 h. The parasite load was also quantified by qPCR. The results indicated that engulfment of L. major promastigotes does not induce any pro-inflammatory cytokines expression by macrophages; however, the infected-cells are capable of responding to the TLRs agonists, and a lesser extent, to the SLA stimulation. Encapsulation resulted in increased strength of the IL-1ß, IL-6, TNF-α, and increased and prolonged time of iNOS expression. Also, encapsulation showed the leishmanicidal activity by decreasing parasite load in treated NPs formulations. Among the different combinations of the components, the triple (SLA-R848-Pam3CSK4) forms promoted the highest activation of macrophages, followed by dual SLA-Pam3CSK4 and SLA-R848 NPs. In conclusion, the findings of this study indicate that the addition of SLA in combination with TLR1/2 and TLR7/8 agonists either in NPs or in soluble forms overcome the suppression of L. major-infected macrophages. Moreover, encapsulation increases the strength and duration of the cytokines and iNOS expression, in parallel with decreasing parasite load, suggesting a longer availability or delivery of the NPs into the macrophages. These findings highlight the advantages of particulate therapeutic vaccine formulations.


Assuntos
Antígenos de Protozoários/farmacologia , Imidazóis/farmacologia , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Lipopeptídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Receptores Toll-Like/agonistas , Tripanossomicidas/farmacologia , Animais , Antígenos de Protozoários/química , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Portadores de Fármacos , Composição de Medicamentos , Interações Hospedeiro-Parasita , Imidazóis/química , Leishmania major/patogenicidade , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/parasitologia , Lipopeptídeos/química , Macrófagos/metabolismo , Macrófagos/parasitologia , Camundongos , Nanopartículas , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Carga Parasitária , Transdução de Sinais , Receptores Toll-Like/metabolismo , Tripanossomicidas/química
14.
Crit Care Med ; 49(3): e315-e326, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481407

RESUMO

OBJECTIVES: Catecholaminergic vasopressors are the cornerstone of circulatory shock management. Nevertheless, catecholamines have problematic side effects, arousing a growing interest in noncatecholaminergic agents such as vasopressin or angiotensin-II. However, their respective effects on sepsis-associated microvascular endothelial dysfunction such as permeability or inflammation remain elusive. We investigated the role of catecholamines and other vasopressors on Toll-like receptor agonists-induced microvascular endothelial permeability and inflammation. SETTING: University research laboratory/cell research. SUBJECTS: Human pulmonary microvascular endothelial cells from multiple donors. INTERVENTION: Confluent monolayers of human pulmonary microvascular endothelial cells were treated with Toll-like receptor agonists (lipopolysaccharide, Poly[I:C], or tripalmitoyl-S-glyceryl cysteine) in the presence or absence of epinephrine, norepinephrine, vasopressin, and angiotensin-II. Permeability was inferred from transendothelial resistance, measured using electrical cell impedance sensing, where decreased transendothelial resistance is consistent with increased permeability. Cell-cell junction molecule expression was assessed via immunofluorescence microscopy and flow cytometry. We quantified cytokines in supernatants of Toll-like receptor agonist-treated human pulmonary microvascular endothelial cells. MEASUREMENTS AND MAIN RESULTS: Epinephrine and norepinephrine both ameliorate lipopolysaccharide, polyinosinic:polycytidylic acid, or tripalmitoyl-S-glyceryl cysteine-induced reductions in transendothelial resistance, a surrogate for endothelial permeability. In contrast, the noncatecholaminergic agents, vasopressin, and angiotensin-II did not affect Toll-like receptor agonists-induced reductions in transendothelial resistance. ß1- and ß2-adrenergic receptor antagonists reduced the effects of the catecholamines on transendothelial resistance, whereas α-adrenergic receptor antagonists did not. We observed that epinephrine and norepinephrine induced actin cytoskeletal rearrangement and normalized the membrane expression of proteins involved with adherens-junctions (vascular endothelial-cadherin) and tight-junctions (zona occludens-1). Despite having a substantial effect on endothelial permeability, epinephrine and norepinephrine did not affect human pulmonary microvascular endothelial cell survival or production of interleukin-8, interleukin-6, or monocyte chemoattractant protein-1 (CCL-2) induced by Toll-like receptor agonists, suggesting that these functions are regulated separately from permeability. CONCLUSIONS: Our findings demonstrate that treatment with epinephrine or norepinephrine strongly reduces endothelial permeability induced by agonists of multiple Toll-like receptors (Toll-like receptor-2, Toll-like receptor-3, Toll-like receptor-4) in vitro. Our studies suggest that both ß1- and ß2-adrenergic receptors mediate the stabilizing effects of epinephrine and norepinephrine on the endothelial barrier.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/metabolismo , Epinefrina/farmacologia , Norepinefrina/farmacologia , Receptores Toll-Like/agonistas , Vasoconstritores/farmacologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Humanos
15.
Cell ; 184(2): 441-459.e25, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33333021

RESUMO

Barrier tissue immune responses are regulated in part by nociceptors. Nociceptor ablation alters local immune responses at peripheral sites and within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Using high-resolution imaging, viral tracing, single-cell transcriptomics, and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is responsive to lymph-borne inflammatory signals. Transcriptomics profiling revealed that multiple sensory neuron subsets, predominantly peptidergic nociceptors, innervate LNs, distinct from those innervating surrounding skin. To uncover LN-resident cells that may interact with LN-innervating sensory neurons, we generated a LN single-cell transcriptomics atlas and nominated nociceptor target populations and interaction modalities. Optogenetic stimulation of LN-innervating sensory fibers triggered rapid transcriptional changes in the predicted interacting cell types, particularly endothelium, stromal cells, and innate leukocytes. Thus, a unique population of sensory neurons monitors peripheral LNs and may locally regulate gene expression.


Assuntos
Imunomodulação , Linfonodos/imunologia , Linfonodos/inervação , Células Receptoras Sensoriais/imunologia , Potenciais de Ação , Animais , Inflamação/patologia , Camundongos , Nociceptores/metabolismo , Optogenética , Peptídeos/metabolismo , Pele/inervação , Sistema Nervoso Simpático/fisiologia , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo
16.
Front Immunol ; 11: 599083, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33281825

RESUMO

Toll-like receptors (TLRs) are essential components of innate immunity and provide defensive inflammatory responses to invading pathogens. Located within the plasma membranes of cells and also intracellular endosomes, TLRs can detect a range of pathogen associated molecular patterns from bacteria, viruses and fungi. TLR activation on dendritic cells can propagate to an adaptive immune response, making them attractive targets for the development of both prophylactic and therapeutic vaccines. In contrast to conventional adjuvants such as aluminium salts, TLR agonists have a clear immunomodulatory profile that favours anti-allergic T lymphocyte responses. Consequently, the potential use of TLRs as adjuvants in Allergen Immunotherapy (AIT) for allergic rhinitis and asthma remains of great interest. Allergic Rhinitis is a Th2-driven, IgE-mediated disease that occurs in atopic individuals in response to exposure to otherwise harmless aeroallergens such as pollens, house dust mite and animal dander. AIT is indicated in subjects with allergic rhinitis whose symptoms are inadequately controlled by antihistamines and nasal corticosteroids. Unlike anti-allergic drugs, AIT is disease-modifying and may induce long-term disease remission through mechanisms involving upregulation of IgG and IgG4 antibodies, induction of regulatory T and B cells, and immune deviation in favour of Th1 responses that are maintained after treatment discontinuation. This process takes up to three years however, highlighting an unmet need for a more efficacious therapy with faster onset. Agonists targeting different TLRs to treat allergy are at different stages of development. Synthetic TLR4, and TLR9 agonists have progressed to clinical trials, while TLR2, TLR5 and TLR7 agonists been shown to have potent anti-allergic effects in human in vitro experiments and in vivo in animal studies. The anti-allergic properties of TLRs are broadly characterised by a combination of enhanced Th1 deviation, regulatory responses, and induction of blocking antibodies. While promising, a durable effect in larger clinical trials is yet to be observed and further long-term studies and comparative trials with conventional AIT are required before TLR adjuvants can be considered for inclusion in AIT. Here we critically evaluate experimental and clinical studies investigating TLRs and discuss their potential role in the future of AIT.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Alérgenos , Asma , Dessensibilização Imunológica , Rinite Alérgica , Receptores Toll-Like , Imunidade Adaptativa , Alérgenos/imunologia , Alérgenos/uso terapêutico , Animais , Asma/imunologia , Asma/terapia , Humanos , Imunidade Inata , Rinite Alérgica/imunologia , Rinite Alérgica/terapia , Receptores Toll-Like/agonistas , Receptores Toll-Like/imunologia
17.
Cells ; 9(12)2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339125

RESUMO

Transplanted mesenchymal stem/stromal cells (MSCs) are a promising and innovative approach in regenerative medicine. Their regenerative potential is partly based upon their immunomodulatory activities. One of the most investigated immunomediators in MSCs, such as in periodontal ligament-derived MSCs (hPDLSCs), is indoleamine-2,3-dioxygenase-1 (IDO-1) which is upregulated by inflammatory stimuli, like cytokines. However, there are no data concerning continuing IDO-1 expression in hPDLSCs after the removal of inflammatory stimuli, such as cytokines and toll-like receptor (TLR) agonist-2 and TLR-3. Hence, primary hPDLSCs were stimulated with interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, TLR-2 agonist Pam3CSK4 or TLR-3 agonist Poly I/C. IDO-1 gene and protein expression and its enzymatic activity were measured up to five days after removing any stimuli. IL-1ß- and TNF-α-induced IDO-1 expression and enzymatic activity decreased in a time-dependent manner after cessation of stimulation. IFN-γ caused a long-lasting effect on IDO-1 up to five days after removing IFN-γ. Both, TLR-2 and TLR-3 agonists induced a significant increase in IDO-1 gene expression, but only TLR-3 agonist induced significantly higher IDO-1 protein expression and enzymatic activity in conditioned media (CM). IDO-1 activity of Poly I/C- and Pam3CSK4-treated hPDLSCs was higher at one day after removal of stimuli than immediately after stimulation and declined to basal levels after five days. Among all tested stimuli, only IFN-γ was able to induce long-lasting IDO-1 expression and activity in hPDLSCs. The high plasticity of IDO-1 expression and its enzymatic activity in hPDLSCs due to the variable cytokine and virulence factor milieu and the temporal-dependent responsiveness of hPDLSCs may cause a highly dynamic potential of hPDLSCs to modulate immune responses in periodontal tissues.


Assuntos
Citocinas/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Ligamento Periodontal/citologia , Células-Tronco/enzimologia , Receptores Toll-Like/agonistas , Células Cultivadas , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Lipopeptídeos/farmacologia , Poli I-C/farmacologia , Células-Tronco/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/enzimologia , Receptores Toll-Like/metabolismo
18.
Front Immunol ; 11: 589833, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240278

RESUMO

Vaccine development utilizing various platforms is one of the strategies that has been proposed to address the coronavirus disease 2019 (COVID-19) pandemic. Adjuvants are critical components of both subunit and certain inactivated vaccines because they induce specific immune responses that are more robust and long-lasting. A review of the history of coronavirus vaccine development demonstrates that only a few adjuvants, including aluminum salts, emulsions, and TLR agonists, have been formulated for the severe acute respiratory syndrome-associated coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and currently the SARS-CoV-2 vaccines in experimental and pre-clinical studies. However, there is still a lack of evidence regarding the effects of the adjuvants tested in coronavirus vaccines. This paper presents an overview of adjuvants that have been formulated in reported coronavirus vaccine studies, which should assist with the design and selection of adjuvants with optimal efficacy and safety profiles for COVID-19 vaccines.


Assuntos
Adjuvantes Imunológicos , Vacinas contra COVID-19 , Alumínio , Emulsões , Humanos , Receptores Toll-Like/agonistas
19.
Acc Chem Res ; 53(10): 2081-2093, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32966047

RESUMO

Recent developments in the fields of biomedical chemistry and immune bioengineering have enabled innovative therapeutic approaches that can enhance the efficacy, accuracy, and safety of cancer immunotherapy. Among the numerous strategies utilized in cancer immunotherapy, Toll-like receptor (TLR) agonist-based approaches have been studied for a long time since they trigger the innate immune system and generate antigen-specific T cell responses to fight against tumors. In addition to these immunostimulatory functions, TLR agonists also contribute to the reprogramming of immune suppressive tumor microenvironments. Although TLR agonists are now being intensively studied in clinical trials due to their substantial immunomodulatory properties, they still show a low therapeutic index. Nonspecific and random stimulation of various immune cells produces excess levels of proinflammatory cytokines, resulting in cytokine storms and chronic diseases. Therefore, the development of chemical strategies to enhance the therapeutic efficacy as well as the safety of TLR agonist-based immunotherapy is essential and in high demand.In this Account, we summarize and discuss recent developments in biomedical chemistry and bioengineering techniques for the immunomodulation of TLR agonists that have addressed the limitations in current cancer immunotherapy. Immunomodulation of TLR agonists can be classified into two different approaches: (1) molecular modulation via chemical structure modification and (2) macroscopic modulation via an engineered drug delivery system. In molecular modulation, based on prodrug and antedrug principles, activity is modulated (active or inactive) through immolative chemical linkers that can respond to extrinsic or intrinsic biological stimulation and the plasmatic environment, respectively. To increase the effectiveness of TLR agonists as immunostimulatory agents, researchers have conjugated TLR agonists with other immunotherapeutic moieties (antigen, antibody, other TLR agonist, etc.). For macroscopic modulation, bioengineering of delivery carriers differing in size or with albumin hitchhiking moieties has been utilized to increase the efficiency of the targeting of these carriers to secondary lymphoid organs (lymph nodes (LNs) and spleen). The conjugation of specific targeting ligands and incorporation of stimulus-triggering moieties can promote the delivery of TLR agonists into specific cells or intracellular compartments. Implantable porous scaffolds for specific immune cell recruitment and in situ depot-forming gel systems for controlled release of immunomodulatory drugs can increase the therapeutic efficacy of TLR agonists while reducing systemic toxicity. Taken together, these findings show that well-designed and precisely controlled chemical strategies for the immunomodulation of TLR agonists at both the molecular and macroscopic levels are expected to play key roles in improving the therapeutic efficacy of cancer immunotherapy while minimizing immune-related toxicity.


Assuntos
Imunoterapia , Neoplasias/terapia , Receptores Toll-Like/agonistas , Portadores de Fármacos/química , Endossomos/imunologia , Endossomos/metabolismo , Humanos , Linfonodos/imunologia , Linfonodos/metabolismo , Nanopartículas/química , Neoplasias/imunologia , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Receptores Toll-Like/metabolismo
20.
Front Immunol ; 11: 1800, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973755

RESUMO

White adipose tissue but recently also brown adipose tissue have emerged as endocrine organs. Age-associated obesity is accompanied by prolonged and elevated lipopolysaccharide (LPS)-induced sickness symptoms and increased cytokine and adipokine levels in the circulation partially originating from adipose tissue. In the present study, ex vivo fat explants were used to investigate how the exogenous pathogen-associated molecular pattern (PAMP) LPS or the endogenous danger-associated molecular patterns (DAMPs) high mobility group box-1 protein (HMGB1) and biglycan modulate the release of cytokines and adipokines/batokines and, thus, could influence systemic and/or local inflammation. The response of adipose tissue (epididymal, retroperitoneal, subcutaneous, and brown) was compared between young lean and old obese rats (2 vs. 24 months old). LPS induced a strong interleukin (IL)-6 and tumor necrosis factor (TNF) alpha release into the supernatant of all adipose tissue types investigated. HMGB1 (subcutaneous) and biglycan (retroperitoneal) led to an increased release of IL-6 and TNFalpha (HMGB1) and decreased visfatin and adiponectin (biglycan) secretion from epididymal adipose tissue (young rats). Visfatin was also decreased by HMGB1 in retroperitoneal adipose tissue of old rats. We found significantly higher leptin (all fat pads) and adiponectin (subcutaneous) levels in supernatants of adipose tissue from old compared to young rats, whereas visfatin secretion showed the opposite. The expression of the biglycan receptor Toll-like receptor (TLR) 2 as well as the LPS and HMGB1 receptors TLR4 and receptor for advanced glycation end products (RAGE) were reduced with age (TLR4/RAGE) and by stimulation with their ligands (subcutaneous). Overall, we revealed that adipokines/adipose-tissue released cytokines show some modulation of their release caused by mediators of septic (batokines) and sterile inflammation with potential implication for acute and chronic disease. Moreover, aging may increase or decrease the release of fat-derived mediators. These data show that DAMPS and LPS locally modulate cytokine secretion while only DAMPS but not LPS can locally alter adipokine secretion during inflammation.


Assuntos
Adipocinas/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Biglicano/farmacologia , Citocinas/metabolismo , Proteína HMGB1/farmacologia , Lipopolissacarídeos/farmacologia , Receptores Toll-Like/agonistas , Tecido Adiposo Marrom/imunologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Fatores Etários , Animais , Masculino , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/agonistas , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Via Secretória , Transdução de Sinais , Técnicas de Cultura de Tecidos , Receptores Toll-Like/metabolismo
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