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1.
Front Immunol ; 12: 719115, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367187

RESUMO

Introduction: Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19. Methods: We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants. Results: TLR7 missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c.644A>G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T>C; p.(Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.


Assuntos
COVID-19/genética , Mutação de Sentido Incorreto , SARS-CoV-2 , Receptor 7 Toll-Like/genética , Adulto , Substituição de Aminoácidos , COVID-19/imunologia , COVID-19/patologia , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Receptor 7 Toll-Like/imunologia
2.
JCI Insight ; 6(18)2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34375313

RESUMO

The inflammatory and IFN pathways of innate immunity play a key role in the resistance and pathogenesis of coronavirus disease 2019 (COVID-19). Innate sensors and SARS-CoV-2-associated molecular patterns (SAMPs) remain to be completely defined. Here, we identified single-stranded RNA (ssRNA) fragments from the SARS-CoV-2 genome as direct activators of endosomal TLR7/8 and MyD88 pathway. The same sequences induced human DC activation in terms of phenotype and function, such as IFN and cytokine production and Th1 polarization. A bioinformatic scan of the viral genome identified several hundreds of fragments potentially activating TLR7/8, suggesting that products of virus endosomal processing potently activate the IFN and inflammatory responses downstream of these receptors. In vivo, SAMPs induced MyD88-dependent lung inflammation characterized by accumulation of proinflammatory and cytotoxic mediators and immune cell infiltration, as well as splenic DC phenotypical maturation. These results identified TLR7/8 as a crucial cellular sensor of ssRNAs encoded by SARS-CoV-2 involved in host resistance and the disease pathogenesis of COVID-19.


Assuntos
COVID-19/virologia , Imunidade Inata , RNA Viral/análise , SARS-CoV-2/genética , Receptor 7 Toll-Like/imunologia , COVID-19/genética , COVID-19/imunologia , Humanos , Pulmão/virologia , SARS-CoV-2/imunologia
3.
Immunology ; 164(2): 372-385, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34077562

RESUMO

Plasmacytoid dendritic cells (pDCs) play a key role in the initiation and amplification of systemic lupus erythematosus (SLE)-associated vascular injury. In this study, we found that dsDNA induced dose- and time-dependent increase in IFN-α and Toll-like receptor 7 (TLR7), TLR9 and IRF7 expression in pDCs. Co-cultured circulating endothelial cells (ECs) with activated pDCs significantly decreased proliferation, tube formation and migration in ECs. The elevated level of cellular IFN-α increased cell adhesion, promoted cell apoptosis, induced cell senescence and arrested cells at G0/G1 phase of endothelial progenitor cells (EPCs). Additionally, the co-culture system activated MAPK and inactivated PI3K. Pristane was used to establish a in vivo SLE-like mouse model. Importantly, we showed that INF-α-neutralizing antibody (IFN-α-NA) rescued all the changes induced by IFN-α in vitro and prevented vascular injury in pristane-induced SLE model in vivo. In conclusion, we confirmed that activated pDCs promoted vascular damage and the dysfunction of ECs/EPCs via IFN-α production. IFN-α-neutralizing antibody may be a clinical implication for preventing vascular injury. PI3K signalling and AMPK signalling were associated with SLE-associated vascular functions.


Assuntos
Proteínas Quinases Ativadas por AMP/imunologia , Anticorpos Neutralizantes/imunologia , Inflamação/imunologia , Interferon-alfa/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Lesões do Sistema Vascular/imunologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Células Endoteliais/imunologia , Feminino , Mediadores da Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor 7 Toll-Like/imunologia
4.
Immunopharmacol Immunotoxicol ; 43(3): 259-264, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34018464

RESUMO

Coronavirus disease 2019 (COVID-19) is associated with irreversible effects on vital organs, especially the respiratory and cardiac systems. While the immune system plays a key role in the survival of patients to viral infections, in COVID-19, there is a hyperinflammatory immune response evoked by all the immune cells, such as neutrophils, monocytes, and includes release of various cytokines, resulting in an exaggerated immune response, named cytokine storm. This severe, dysregulated immune response causes multi-organ damage, which eventually leads to high mortality. One of the most important components of hypersensitivity is immunoglobulin E (IgE), which plays a major role in susceptibility to respiratory infections and can lead to the activation of mast cells. There is also a negative association between IgE and IFN-α, which can reduce Toll-like receptor (TLR) nine receptor expression and TLR-7 signaling to disrupt IFN production. Moreover, anti-IgE drugs such as omalizumab reduces the severity and duration of COVID-19. In addition to its anti-IgE effect, omalizumab inhibits inflammatory cells such as neutrophils. Hence, blockade of IgE may have clinical utility as an immunotherapy for COVID-19.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/imunologia , Omalizumab/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Humanos , Imunoglobulina E/imunologia , Interferon-alfa/imunologia , Omalizumab/imunologia , Transdução de Sinais/imunologia , Receptor 7 Toll-Like/imunologia
5.
Chem Commun (Camb) ; 57(38): 4698-4701, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977971

RESUMO

Despite the ease of production and improved safety profiles of recombinant vaccines, the inherently low immunogenicity of unadjuvanted proteins remains an impediment to their widespread adoption. The covalent tethering of TLR agonists to antigenic proteins offers a unique approach to co-deliver both constituents to the same cell-enhancing vaccine efficacy while minimizing reactogenicity. However, the paucity of simple and effective linker chemistries continues to hamper progress. Here, we present a modular, PEG-based linker system compatible with even extremely lipophilic and challenging TLR7/8 agonists. To advance the field and address previous obstacles, we offer the most straightforward and antigen-preserving linker system to date. These antigen-adjuvant conjugates enhance antigen-specific immune responses in mice, demonstrating the power of our approach within the context of modern vaccinology.


Assuntos
Antígenos/imunologia , Glicoproteínas de Membrana/imunologia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Adjuvantes Imunológicos , Animais , Camundongos
6.
Am J Respir Cell Mol Biol ; 65(3): 309-318, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34003734

RESUMO

Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33-induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33-induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33-induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1-deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33-induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma.


Assuntos
Imidazóis/farmacologia , Imunidade Inata/efeitos dos fármacos , Interleucinas/imunologia , Pulmão/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Glicoproteínas de Membrana/agonistas , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/agonistas , Animais , Asma/genética , Asma/imunologia , Asma/patologia , Quimiocina CCL17/genética , Quimiocina CCL17/imunologia , Quimiocina CCL24/genética , Quimiocina CCL24/imunologia , Eosinófilos/imunologia , Eosinófilos/patologia , Imunidade Inata/genética , Inflamação/genética , Inflamação/imunologia , Interleucina-33/genética , Interleucina-33/imunologia , Interleucinas/genética , Pulmão/patologia , Linfócitos/patologia , Macrófagos/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Interleucina/deficiência , Receptores de Interleucina/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia
7.
J Innate Immun ; 13(6): 345-358, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34058746

RESUMO

Regulation of proinflammatory cytokine expression is critical in the face of single-stranded RNA (ssRNA) virus infections. Many viruses, including coronavirus and influenza virus, wreak havoc on the control of cytokine expression, leading to the formation of detrimental cytokine storms. Understanding the regulation and interplay between inflammatory cytokines is critical to the identification of targets involved in controlling the induction of cytokine expression. In this study, we focused on how the antiviral cytokine interleukin-27 (IL-27) regulates signal transduction downstream of Toll-like receptor 7 (TLR7) and TLR8 ligation, which recognize endosomal single-stranded RNA. Given that IL-27 alters bacterial-sensing TLR expression on myeloid cells and can inhibit replication of single-stranded RNA viruses, we investigated whether IL-27 affects expression and function of TLR7 and TLR8. Analysis of IL-27-treated THP-1 monocytic cells and THP-1-derived macrophages revealed changes in mRNA and protein expression of TLR7 and TLR8. Although treatment with IL-27 enhanced TLR7 expression, only TLR8-mediated cytokine secretion was amplified. Furthermore, we demonstrated that imiquimod, a TLR7 agonist, inhibited cytokine and chemokine production induced by a TLR8 agonist, TL8-506. Delineating the immunomodulatory role of IL-27 on TLR7 and TLR8 responses provides insight into how myeloid cell TLR-mediated responses are regulated during virus infection.


Assuntos
Interleucina-27/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Citocinas/imunologia , Humanos , Imunomodulação , Inflamação , RNA Mensageiro/metabolismo , Transdução de Sinais , Células THP-1 , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/metabolismo
8.
Mol Immunol ; 134: 183-191, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33812250

RESUMO

Interferon regulatory factor 7 (IRF7) is a crucial regulator of type I interferons (IFNs) against pathogen infections and plays a significant role in the endosomal Toll-like receptor signaling (namely, TLR7 and TLR9) in plasmacytoid dendritic cells (pDCs). In this study, we identify MEKK3, one of the MAP3K kinase, as a potent stimulator of IRF7 upon cellular activation of the TLR7/9 signaling pathways to induce various type I IFNs. The knockdown of MEKK3 in vivo substantially impairs type I IFN induction and increases susceptibility to HSV-1 infection in mice. Overexpression of MEKK3 significantly activates IRF7 to trigger strong induction of type I IFNs, while cells deficient in MEKK3 expression show abrogated innate immune responses to TLR7/TLR9 ligands stimulation. We confirmed that the IFNs' induction is due to a MEKK3 and IRF7 interaction; it leads to the phosphorylation of IRF7 at multiple sites. Moreover, endogenous MEKK3 can bind and phosphorylate IRF7 after TLR9 activation by its specific ligand CpG DNA. It is the first time to report the role of MEKK3 on type I IFN, which indicates crosstalk between MAP3K activation and type I IFNs' induction in the endosomal Toll-like receptor pathways.


Assuntos
Fator Regulador 7 de Interferon/metabolismo , Interferon Tipo I/biossíntese , MAP Quinase Quinase Quinase 3/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , Linhagem Celular , Feminino , Humanos , Fator Regulador 7 de Interferon/imunologia , Interferon Tipo I/imunologia , MAP Quinase Quinase Quinase 3/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia , Receptor 7 Toll-Like/imunologia , Receptor Toll-Like 9/imunologia
9.
Cell ; 184(7): 1790-1803.e17, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33735607

RESUMO

The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here, we show XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c+ atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine.


Assuntos
Linfócitos B/imunologia , COVID-19 , Lúpus Eritematoso Sistêmico , RNA Longo não Codificante/fisiologia , Receptor 7 Toll-Like/imunologia , Inativação do Cromossomo X , COVID-19/genética , COVID-19/imunologia , Linhagem Celular , Metilação de DNA , Feminino , Inativação Gênica , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia
10.
Science ; 371(6534)2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33707237

RESUMO

Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.


Assuntos
Apresentação do Antígeno , Autoimunidade , Coagulação Sanguínea/imunologia , Receptor de Proteína C Endotelial/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lisofosfolipídeos/imunologia , Monoglicerídeos/imunologia , Animais , Anticorpos Antifosfolipídeos/biossíntese , Autoanticorpos/biossíntese , Modelos Animais de Doenças , Perda do Embrião/imunologia , Endossomos/imunologia , Receptor de Proteína C Endotelial/genética , Humanos , Imunidade Inata , Lúpus Eritematoso Sistêmico/sangue , Camundongos , Camundongos Mutantes , Esfingomielina Fosfodiesterase/metabolismo , Trombose/imunologia , Receptor 7 Toll-Like/imunologia
11.
Benef Microbes ; 12(1): 85-93, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33550937

RESUMO

Several studies have demonstrated a decrease in upper respiratory infection (URI) frequency and severity in subjects taking probiotic supplements. We hypothesised beneficial effects of probiotics on viral URI in children are due to modulation of inflammatory innate immune responses. We tested this hypothesis, providing children with a probiotic combination of Lactobacillus acidophilus/Bidfidobacterium animalis ssp. lactis Bi-07 (NCFM/Bi-07) and measuring levels of cytokines in response to stimulation of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 7/8 agonist resiquimod (R848). In this open label study, 21 (2 dropouts) children received probiotic containing 5×109 cfu each of NCFM/(Bi-07) daily for 30 days. Whole blood was taken from each subject at study entry and 30 days for culture of PBMCs. PBMCs stimulated with resiquimod (R848) or unstimulated were incubated and a panel of immune markers was measured. There was a significant decrease in the net (stimulated-null) level of myeloid progenitor inhibitory factor 1 (MPIF-1) (mean decrease 0.1 ng/ml, 95% confidence interval 0.01-0.24, P=0.032) following probiotic supplementation. The change in immune marker levels after supplementation, when analysed together with respect to expected inflammatory/anti-inflammatory effects, was increased for interleukin (IL)-10 and decreased for MPIF-1, IL-8, interferon gamma induced protein 10, macrophage inflammatory protein 3 alpha (MIP-3α) and E-selectin (P=0.01). Adverse events were mild. In conclusion, supplementation with this probiotic combination was safe and resulted in significant modulation of PBMC limited immune response to TLR7/8 agonist R848 and in levels of MPIF-1 and MIP-3α. The anti-inflammatory effect may be one mechanism by which probiotics modulate the immune system however further study is needed.


Assuntos
Bifidobacterium animalis/fisiologia , Imidazóis/administração & dosagem , Lactobacillus acidophilus/fisiologia , Leucócitos Mononucleares/efeitos dos fármacos , Probióticos/administração & dosagem , Infecções Respiratórias/tratamento farmacológico , Pré-Escolar , Feminino , Humanos , Imunidade Inata , Lactente , Interleucina-10/genética , Interleucina-10/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/imunologia
12.
Sci Rep ; 11(1): 3346, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558639

RESUMO

There is a significant interest in designing therapeutic agents that can enhance ADCC and thereby improve clinical responses with approved antibodies. We recently reported the combination of an imidazoquinoline-based TLR7/8 agonist (522) with a monoclonal antibody improved ADCC in vitro and in vivo. In the present study, we tested several new small molecule TLR7/8 agonists that induce significantly higher cytokines compared to both the FDA-approved TLR7 agonist, imiquimod, and 522. We evaluated these agonists in combination with monoclonal antibody therapy, with the main goal of enhancing ADCC. Our studies show these TLR7/8 agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. Specifically, we found the agonists 574 and 558 significantly enhanced NK cell-mediated ADCC in vitro as well as enhanced the anti-cancer efficacy of monoclonal antibodies in two different in vivo mouse models. Additionally, we found the agonists were able to stimulate CD8 T cells, likely indicative of an early adaptive immune response.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Imiquimode/farmacologia , Células Matadoras Naturais/imunologia , Neoplasias Experimentais , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Células A549 , Animais , Humanos , Células Matadoras Naturais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Mol Sci ; 22(3)2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33498655

RESUMO

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.


Assuntos
Doenças Autoimunes/genética , Imunidade/genética , Inativação do Cromossomo X , Animais , Cromossomos Humanos X , Feminino , Histona Desmetilases/genética , Histona Desmetilases/imunologia , Histona Desmetilases/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/imunologia
14.
Eur J Immunol ; 51(3): 714-720, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33079387

RESUMO

Thirty percent of psoriasis patients develop psoriatic arthritis (PsA), nevertheless the mechanism remains unknown. Endogenous GU-rich miRNAs activate endosomal TLR7 that plays a critical role in autoimmune diseases. We found that endogenous TLR7 ligands, miR-29 and miR-Let7b, were markedly increased in PsA compared to osteoarthritis (OA) synovial fluid (SF)s. We showed that intradermal (i.d.) miR-Let7b injection promoted skin inflammation, which was characterized by amplified Th1 cells, CD68+ M1 macrophages, and transcriptional upregulation of glycolytic mediators, GLUT1, C-MYC, and HIF1α. Expansion of skin Th1 cells driven by miR-Let7b was also linked to elevated M1-associated IRFs. Interestingly, i.d. miR-Let7b administration exacerbated suboptimal joint inflammation along with metabolic reconfiguration of the PsA-like preclinical model. Moreover, TLR7 agonist, R837, potentiated metabolic reprogramming and expression of IL-1ß, IL-6, and IL-12 in murine macrophages, enabling myeloid-to-T-cell crosstalk. Consistently, treatment with glycolytic inhibitors, 2-DG and/or HIF1αi, reversed R837-induced metabolic remodeling and disrupted the TLR7-driven inflammatory phenotype in myeloid and lymphoid cells. Similar to miR-Let7b, R837 also differentiates progenitor cells into mature osteoclasts, primarily through RANKL induction. Taken together, this study indicates that TLR7-instigated metabolic rewiring of macrophages and their cross-regulation of T cells connects skin immunopathology to joint inflammation.


Assuntos
Artrite Psoriásica/imunologia , Articulações/imunologia , Macrófagos/imunologia , Pele/imunologia , Receptor 7 Toll-Like/imunologia , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Citocinas/imunologia , Humanos , Inflamação/imunologia , Ligantes , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos DBA , MicroRNAs/imunologia , Células Mieloides/imunologia , Osteoclastos/imunologia , Transdução de Sinais/imunologia , Líquido Sinovial/imunologia , Células Th1/imunologia
15.
J Ethnopharmacol ; 268: 113555, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33152425

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Carvacrol, a monoterpene phenol from Mosla chinensis Maxim, which is a commonly Chinese herbal medicine. The most important pharmacology of it is dispelling exogenous evils by increasing perspiration. And it is the gentleman medicine in the Chinese herbal compound prescription of Xin-Jia-Xiang-Ru-Yin, mainly for the treatment of summer colds with dampness including influenza virus A infection. AIM OF THE STUDY: Our preliminary study verified that the Xin-Jia-Xiang-Ru-Yin could inhibit acute lung injury of mice with influenza virus A infection. And there have been some reports implicating the high antimicrobial activity of carvacrol for a wide range of product preservation, but little research including the effects of it on viral infection. The aim of this study was to reveal the antiviral effects of carvacrol, the main constituent in Mosla chinensis Maxim. MATERIALS AND METHODS: Initially, C57BL/6 mice were grouped and intranasally administered FM1 virus to construct viral infection models. After treatment with ribavirin and carvacrol for 5 days, all mice were euthanized, and specimens were immediately obtained. Histology, flow cytometry and Meso Scale Discovery (MSD) analysis were used to analyze pathological changes in lung tissue, the expression levels of cytokines and the differentiation and proportion of CD4+ T cells subsets, while Western blot and qRT-PCR were used to detect the expression of related proteins and mRNA. RESULTS: Carvacrol attenuated lung tissue damage, the proportions of Th1, Th2, Th17 and Treg in CD4+ T cells and the relative proportions of Th1/Th2 and Th17/Treg cells. Carvacrol inhibited the expression of inflammation-associated cytokines including IFN-γ, IL-2, IL-4, IL-5, IL-12 and TNF-ɑ, IL-1, IL-10, IL-6. Decreased levels of TLR7, MyD88, IRAK4, TRAK6, NF-κB, RIG-I, IPS-I and IRF mRNA in carvacrol-treated mice were observed comparing to the mice in VC group. Further, the total expression of RIG-I, MyD88 and NF-κB proteins had increased significantly in the VC group but reduced obviously in the group treated with ribavirin or carvacrol. CONCLUSIONS: These results indicate that carvacrol is a potential alternative treatment for the excessive immune response induced by influenza virus A infection, the cold-fighting effect of Mosla chinensis Maxim may depend on the anti-virus of carvacrol.


Assuntos
Cimenos/farmacologia , Proteína DEAD-box 58/antagonistas & inibidores , Imunidade Inata/efeitos dos fármacos , Influenzavirus A/efeitos dos fármacos , Glicoproteínas de Membrana/antagonistas & inibidores , Receptor 7 Toll-Like/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Animais , Cimenos/uso terapêutico , Proteína DEAD-box 58/imunologia , Proteína DEAD-box 58/metabolismo , Feminino , Imunidade Inata/imunologia , Influenzavirus A/imunologia , Influenzavirus A/metabolismo , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Receptor 7 Toll-Like/imunologia , Receptor 7 Toll-Like/metabolismo , Replicação Viral/imunologia
16.
Scand J Immunol ; 93(5): e13019, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33377182

RESUMO

CD8+ T cells are critical to combat pathogens and eradicate malignantly transformed cells. To exert their effector function and kill target cells, T cells produce copious amounts of effector molecules, including the pro-inflammatory cytokines interferon γ, tumour necrosis factor α and interleukin 2. TCR triggering alone is sufficient to induce cytokine secretion by effector and memory CD8+ T cells. However, T cells can also be directly activated by pathogen-derived molecules, such as through the triggering of Toll-like receptors (TLRs). TLR-mediated pathogen sensing by T cells results in the production of only interferon γ. However, in particular when the antigen load on target cells is low, or when TCR affinity to the antigen is limited, antigen-experienced T cells can benefit from costimulatory signals. TLR stimulation can also function in a costimulatory fashion to enhance TCR triggering. Combined TCR and TLR triggering enhances the proliferation, memory formation and effector function of T cells, resulting in enhanced production of interferon γ, tumour necrosis factor α and interleukin 2. Therefore, TLR ligands or the exploitation of TLR signalling could provide novel opportunities for immunotherapy approaches. In fact, CD19 CAR T cells bearing an intracellular TLR2 costimulatory domain were recently employed to treat cancer patients in a clinical trial. Here, the current knowledge regarding TLR2/7 stimulation-induced cytokine production by T cells is reviewed. Specifically, the transcriptional and post-transcriptional pathways engaged upon TLR2/7 sensing and TLR2/7 signalling are discussed. Finally, the potential uses of TLRs to enhance the anti-tumor effector function of T cells are explored.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Receptor 2 Toll-Like/imunologia , Receptor 7 Toll-Like/imunologia , Humanos , Interferon gama/metabolismo , Ativação Linfocitária/imunologia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
17.
Nat Rev Rheumatol ; 17(2): 98-108, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33339987

RESUMO

B lymphocytes have a central role in autoimmune diseases, which are often defined by specific autoantibody patterns and feature a loss of B cell tolerance. A prototypic disease associated with B cell hyperactivity is systemic lupus erythematosus (SLE). In patients with SLE, the loss of B cell tolerance to autoantigens is controlled in a cell-intrinsic manner by Toll-like receptors (TLRs), which sense nucleic acids in endosomes. TLR7 drives the extrafollicular B cell response and the germinal centre reaction that are involved in autoantibody production and disease pathogenesis. Surprisingly, TLR9 seems to protect against SLE, even though it is required for the production of autoantibodies recognizing double-stranded DNA-associated antigens, which are abundant in SLE and are a hallmark of this disease. The protective function of TLR9 is at least partly mediated by its capacity to limit the stimulatory activity of TLR7. The roles of TLR7 and TLR9 in the effector function of B cells in lupus-like disease and in patients with SLE, and the unique features of TLR signalling in B cells, suggest that targeting TLR signalling in SLE might be therapeutically beneficial.


Assuntos
Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores Toll-Like/metabolismo , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Linfócitos B/fisiologia , Humanos , Camundongos , Transdução de Sinais , Receptor 7 Toll-Like/imunologia , Receptor Toll-Like 9/imunologia
18.
Immunity ; 54(2): 235-246.e5, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33357409

RESUMO

The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions.


Assuntos
Células Dendríticas/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Proteína ADAM17 , Animais , Diferenciação Celular , Imunidade Humoral , Imunoglobulina M/imunologia , Inflamação , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Interleucina-6/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasmócitos/imunologia , Receptores de Interleucina-6/sangue , Receptores de Interleucina-6/imunologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Receptor 7 Toll-Like/imunologia
19.
Nucleic Acids Res ; 48(22): 12833-12844, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33275131

RESUMO

RNA modifications are a well-recognized way of gene expression regulation at the post-transcriptional level. Despite the importance of this level of regulation, current knowledge on modulation of tRNA modification status in response to stress conditions is far from being complete. While it is widely accepted that tRNA modifications are rather dynamic, such variations are mostly assessed in terms of total tRNA, with only a few instances where changes could be traced to single isoacceptor species. Using Escherichia coli as a model system, we explored stress-induced modulation of 2'-O-methylations in tRNAs by RiboMethSeq. This analysis and orthogonal analytical measurements by LC-MS show substantial, but not uniform, increase of the Gm18 level in selected tRNAs under mild bacteriostatic antibiotic stress, while other Nm modifications remain relatively constant. The absence of Gm18 modification in tRNAs leads to moderate alterations in E. coli mRNA transcriptome, but does not affect polysomal association of mRNAs. Interestingly, the subset of motility/chemiotaxis genes is significantly overexpressed in ΔTrmH mutant, this corroborates with increased swarming motility of the mutant strain. The stress-induced increase of tRNA Gm18 level, in turn, reduced immunostimulation properties of bacterial tRNAs, which is concordant with the previous observation that Gm18 is a suppressor of Toll-like receptor 7 (TLR7)-mediated interferon release. This documents an effect of stress induced modulation of tRNA modification that acts outside protein translation.


Assuntos
Imunidade Inata/genética , Processamento Pós-Transcricional do RNA/genética , RNA de Transferência/genética , Receptor 7 Toll-Like/genética , Escherichia coli/genética , Regulação da Expressão Gênica/genética , Guanosina/genética , Guanosina/imunologia , Humanos , Interferons/genética , Interferons/imunologia , Metilação , Processamento Pós-Transcricional do RNA/imunologia , RNA de Transferência/imunologia , Receptor 7 Toll-Like/imunologia
20.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322152

RESUMO

Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. The innate immune signals driving lymphocytic infiltration of these glands are not well-defined. Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice. We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development. TLR7 was required for male-specific lacrimal gland inflammation but not for female-specific salivary gland inflammation. Moreover, TLR7 was required for type 1 diabetes development in male but not female NOD mice. RNA sequencing demonstrated that TLR7 was associated with a type I interferon (IFN) response and a type I IFN-independent B cell response in the lacrimal glands. Together these studies identify a previously unappreciated pathogenic role for TLR7 in lacrimal gland autoimmunity and T1D development in male NOD mice adding to the growing body of evidence supporting sex differences in mechanisms of autoimmune disease in NOD mice.


Assuntos
Autoimunidade/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Aparelho Lacrimal/imunologia , Glicoproteínas de Membrana/imunologia , Síndrome de Sjogren/imunologia , Receptor 7 Toll-Like/imunologia , Animais , Linfócitos B/imunologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interferon Tipo I/metabolismo , Aparelho Lacrimal/citologia , Aparelho Lacrimal/patologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , RNA-Seq , Glândulas Salivares/citologia , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Sexo , Receptor 7 Toll-Like/genética
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