RESUMO
Tuberculosis (TB), caused by Mycobacterium tuberculosis ( M. tb), remains one of the leading causes of fatal infectious diseases worldwide. The only licensed vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), has variable efficacy against TB in adults. Insufficiency of immune cell function diminishes the protective effects of the BCG vaccine. It is critical to clarify the mechanism underlying the antimycobacterial immune response during BCG vaccination. Macrophage mannose receptor (MR) is important for enhancing the uptake and processing of glycoconjugated antigens from pathogens for presentation to T cells, but the roles of macrophage MR in the BCG-induced immune response against M. tb are not yet clear. Here, we discover that macrophage MR deficiency impairs the antimycobacterial immune response in BCG-vaccinated mice. Mechanistically, macrophage MR triggers JAK-STAT1 signaling, which promotes antigen presentation via upregulated MHC-II and induces IL-12 production by macrophages, contributing to CD4 + T cell activation and IFN-γ production. MR deficiency in macrophages reduces the vaccine efficacy of BCG and increases susceptibility to M. tb H37Ra challenge in mice. Our results suggest that MR is critical for macrophage antigen presentation and the antimycobacterial immune response to BCG vaccination and offer valuable guidance for the preventive strategy of BCG immunization.
Assuntos
Apresentação de Antígeno , Vacina BCG , Janus Quinases , Lectinas Tipo C , Macrófagos , Receptor de Manose , Lectinas de Ligação a Manose , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis , Receptores de Superfície Celular , Fator de Transcrição STAT1 , Animais , Vacina BCG/imunologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Apresentação de Antígeno/imunologia , Camundongos , Lectinas de Ligação a Manose/imunologia , Lectinas de Ligação a Manose/metabolismo , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Mycobacterium tuberculosis/imunologia , Janus Quinases/metabolismo , Janus Quinases/imunologia , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinação , Camundongos Knockout , FemininoRESUMO
Severe mortality due to the COVID-19 pandemic resulted from the lack of effective treatment. Although COVID-19 vaccines are available, their side effects have become a challenge for clinical use in patients with chronic diseases, especially cancer patients. In the current report, we applied network pharmacology and systematic bioinformatics to explore the use of biochanin A in patients with colorectal cancer (CRC) and COVID-19 infection. Using the network pharmacology approach, we identified two clusters of genes involved in immune response (IL1A, IL2, and IL6R) and cell proliferation (CCND1, PPARG, and EGFR) mediated by biochanin A in CRC/COVID-19 condition. The functional analysis of these two gene clusters further illustrated the effects of biochanin A on interleukin-6 production and cytokine-cytokine receptor interaction in CRC/COVID-19 pathology. In addition, pathway analysis demonstrated the control of PI3K-Akt and JAK-STAT signaling pathways by biochanin A in the treatment of CRC/COVID-19. The findings of this study provide a therapeutic option for combination therapy against COVID-19 infection in CRC patients.
Assuntos
Anticarcinógenos/uso terapêutico , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Neoplasias Colorretais/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genisteína/uso terapêutico , Fitoestrógenos/uso terapêutico , Atlas como Assunto , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/virologia , Ciclina D1/genética , Ciclina D1/imunologia , Receptores ErbB/genética , Receptores ErbB/imunologia , Humanos , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Janus Quinases/genética , Janus Quinases/imunologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Terapia de Alvo Molecular/métodos , Família Multigênica , Farmacologia em Rede/métodos , PPAR gama/genética , PPAR gama/imunologia , Farmacogenética/métodos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/patogenicidade , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de SinaisRESUMO
The tumor microenvironment (TME) is composed of a heterogenous population of cells that exist alongside the extracellular matrix and soluble components. These components can shape an environment that is conducive to tumor growth and metastatic spread. It is well-established that stromal cancer-associated fibroblasts (CAFs) in the TME play a pivotal role in creating and maintaining a growth-permissive environment for tumor cells. A growing body of work has uncovered that tumor cells recruit and educate CAFs to remodel the TME, however, the mechanisms by which this occurs remain incompletely understood. Recent studies suggest that the signal transducer and activator of transcription 3 (STAT3) is a key transcription factor that regulates the function of CAFs, and their crosstalk with tumor and immune cells within the TME. CAF-intrinsic STAT3 activity within the TME correlates with tumor progression, immune suppression and eventually the establishment of metastases. In this review, we will focus on the roles of STAT3 in regulating CAF function and their crosstalk with other cells constituting the TME and discuss the utility of targeting STAT3 within the TME for therapeutic benefit.
Assuntos
Fibroblastos Associados a Câncer/imunologia , Neoplasias/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Fibroblastos Associados a Câncer/metabolismo , Comunicação Celular/imunologia , Progressão da Doença , Humanos , Janus Quinases/imunologia , Janus Quinases/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Fosforilação/imunologia , Fator de Transcrição STAT3/metabolismoRESUMO
STAT proteins represent an important family of evolutionarily conserved transcription factors that play key roles in diverse biological processes, notably including blood and immune cell development and function. Classically, STAT proteins have been viewed as inducible activators of transcription that mediate cellular responses to extracellular signals, particularly cytokines. In this 'canonical' paradigm, latent STAT proteins become tyrosine phosphorylated following receptor activation, typically via downstream JAK proteins, facilitating their dimerization and translocation into the nucleus where they bind to specific sequences in the regulatory region of target genes to activate transcription. However, growing evidence has challenged this paradigm and identified alternate 'non-canonical' functions, such as transcriptional repression and roles outside the nucleus, with both phosphorylated and unphosphorylated STATs involved. This review provides a revised framework for understanding the diverse kaleidoscope of STAT protein functional modalities. It further discusses the implications of this framework for our understanding of STAT proteins in normal blood and immune cell biology and diseases such as cancer, and also provides an evolutionary context to place the origins of these alternative functional modalities.
Assuntos
Neoplasias/imunologia , Fatores de Transcrição STAT/imunologia , Animais , Humanos , Imunidade , Janus Quinases/imunologia , Janus Quinases/metabolismo , Neoplasias/metabolismo , Fosforilação , Fatores de Transcrição STAT/metabolismo , Transdução de SinaisRESUMO
The unprecedented successes of immunotherapies (IOs) including immune checkpoint blockers (ICBs) and adoptive T-cell therapy (ACT) in patients with late-stage cancer provide proof-of-principle evidence that harnessing the immune system, in particular T cells, can be an effective approach to eradicate cancer. This instills strong interests in understanding the immunomodulatory effects of radiotherapy (RT), an area that was actually investigated more than a century ago but had been largely ignored for many decades. With the "newly" discovered immunogenic responses from RT, numerous endeavors have been undertaken to combine RT with IOs, in order to bolster anti-tumor immunity. However, the underlying mechanisms are not well defined, which is a subject of much investigation. We therefore conducted a systematic literature search on the molecular underpinnings of RT-induced immunomodulation and IOs, which identified the IFN-JAK-STAT pathway as a major regulator. Our further analysis of relevant studies revealed that the signaling strength and duration of this pathway in response to RT and IOs may determine eventual immunological outcomes. We propose that strategic targeting of this axis can boost the immunostimulatory effects of RT and radiosensitizing effects of IOs, thereby promoting the efficacy of combination therapy of RT and IOs.
Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Radioterapia/métodos , Linfócitos T/imunologia , Terapia Combinada , Humanos , Interferons/imunologia , Interferons/metabolismo , Janus Quinases/imunologia , Janus Quinases/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Fatores de Transcrição STAT/imunologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/metabolismoRESUMO
Since its discovery, the Janus kinase-signal transduction and activation of transcription (JAK-STAT) pathway has become recognized as a central mediator of widespread and varied human physiological processes. The field of JAK-STAT biology, particularly its clinical relevance, continues to be shaped by 2 important advances. First, the increased use of genomic sequencing has led to the discovery of novel clinical syndromes caused by mutations in JAK and STAT genes. This has provided insights regarding the consequences of aberrant JAK-STAT signaling for immunity, lymphoproliferation, and malignancy. In addition, since the approval of ruxolitinib and tofacitinib, the therapeutic use of JAK inhibitors (jakinibs) has expanded to include a large spectrum of diseases. Efficacy and safety data from over a decade of clinical studies have provided additional mechanistic insights while improving the care of patients with inflammatory and neoplastic conditions. This review discusses major advances in the field, focusing on updates in genetic diseases and in studies of clinical jakinibs in human disease.
Assuntos
Doenças Genéticas Inatas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/imunologia , Fatores de Transcrição STAT/imunologia , Animais , Citocinas/imunologia , Doenças Genéticas Inatas/imunologia , Humanos , Janus Quinases/genética , Mutação , Fatores de Transcrição STAT/genética , Transdução de SinaisRESUMO
Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well.
Assuntos
Antirreumáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Fator Inibidor de Leucemia/farmacologia , Mutação , Retina/efeitos dos fármacos , Retinose Pigmentar/tratamento farmacológico , Rodopsina/genética , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/imunologia , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/patologia , NF-kappa B/genética , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Retina/imunologia , Retina/patologia , Retinose Pigmentar/genética , Retinose Pigmentar/imunologia , Retinose Pigmentar/patologia , Rodopsina/deficiência , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de Sinais , Transgenes , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Rheumatoid arthritis (RA) is characterized by systemic synovitis leading to joint destruction in which imbalances in pro-inflammatory and anti-inflammatory cytokines promote the induction of autoimmunity. Some pro-inflammatory cytokines can trigger the signaling pathways which responsible for immune-mediated inflammation in RA, and the activated signaling pathways produce pro-inflammatory cytokines, resulting in aggravation of RA. Hence, understanding of the signaling pathways and their inhibitors might be advantageous in the development of therapeutic targets and new drugs for RA. In the current review, we summarize the signaling pathways involved in the pathogenesis of RA as well as the potential role of specific inhibitors in its management. We hope this paper may serve a reference for future studies on signaling pathways implicated in the pathogenesis of RA and benefit the treatment of RA.
Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Transdução de Sinais/imunologia , Artrite Reumatoide/etiologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Inibidores de Janus Quinases/farmacologia , Janus Quinases/imunologia , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Modelos Imunológicos , NF-kappa B/antagonistas & inibidores , NF-kappa B/imunologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
SARS-CoV-2 infection causes broad-spectrum immunopathological disease, exacerbated by inflammatory co-morbidities. A better understanding of mechanisms underpinning virus-associated inflammation is required to develop effective therapeutics. Here, we discover that SARS-CoV-2 replicates rapidly in lung epithelial cells despite triggering a robust innate immune response through the activation of cytoplasmic RNA sensors RIG-I and MDA5. The inflammatory mediators produced during epithelial cell infection can stimulate primary human macrophages to enhance cytokine production and drive cellular activation. Critically, this can be limited by abrogating RNA sensing or by inhibiting downstream signalling pathways. SARS-CoV-2 further exacerbates the local inflammatory environment when macrophages or epithelial cells are primed with exogenous inflammatory stimuli. We propose that RNA sensing of SARS-CoV-2 in lung epithelium is a key driver of inflammation, the extent of which is influenced by the inflammatory state of the local environment, and that specific inhibition of innate immune pathways may beneficially mitigate inflammation-associated COVID-19.
Assuntos
COVID-19/imunologia , Proteína DEAD-box 58/imunologia , Células Epiteliais/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Macrófagos/imunologia , RNA Viral/imunologia , Receptores Imunológicos/imunologia , SARS-CoV-2 , COVID-19/genética , COVID-19/virologia , Linhagem Celular , Citocinas/genética , Citocinas/imunologia , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Inflamação/genética , Inflamação/imunologia , Inflamação/virologia , Janus Quinases/imunologia , Pulmão/citologia , Pulmão/imunologia , Pulmão/virologia , Ativação de Macrófagos , NF-kappa B/imunologia , Mucosa Respiratória/citologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/virologia , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Fatores de Transcrição STAT/imunologia , Replicação ViralRESUMO
Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III interferon (IFN), which enhances the immunogenicity of RNA vaccines but can also lead to inhibition of translation. In this study, we screened a library of saRNA constructs with cis-encoded innate inhibiting proteins (IIPs) and determined the effect on protein expression and immunogenicity. We observed that the PIV-5 V and Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a proteins enhance protein expression 100- to 500-fold in vitro in IFN-competent HeLa and MRC5 cells. We found that the MERS-CoV ORF4a protein partially abates dose nonlinearity in vivo, and that ruxolitinib, a potent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor, but not the IIPs, enhances protein expression of saRNA in vivo. Both the PIV-5 V and MERS-CoV ORF4a proteins were found to enhance the percentage of resident cells in human skin explants expressing saRNA and completely rescued dose nonlinearity of saRNA. Finally, we observed that the MERS-CoV ORF4a increased the rabies virus (RABV)-specific immunoglobulin G (IgG) titer and neutralization half-maximal inhibitory concentration (IC50) by â¼10-fold in rabbits, but not in mice or rats. These experiments provide a proof of concept that IIPs can be directly encoded into saRNA vectors and effectively abate the nonlinear dose dependency and enhance immunogenicity.
Assuntos
Imunidade Inata/efeitos dos fármacos , Imunogenicidade da Vacina , Biossíntese de Proteínas/efeitos dos fármacos , Vacinas Sintéticas/farmacologia , Proteínas do Envelope Viral/administração & dosagem , Animais , Linhagem Celular , Vírus da Encefalite Equina Venezuelana/efeitos dos fármacos , Vírus da Encefalite Equina Venezuelana/imunologia , Vírus da Encefalite Equina Venezuelana/patogenicidade , Fibroblastos , Regulação da Expressão Gênica , Células HeLa , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunoglobulina G/biossíntese , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/imunologia , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , NF-kappa B/genética , NF-kappa B/imunologia , Nitrilas , Vírus da Parainfluenza 5/efeitos dos fármacos , Vírus da Parainfluenza 5/imunologia , Vírus da Parainfluenza 5/patogenicidade , Pirazóis/farmacologia , Pirimidinas , Coelhos , Vírus da Raiva/efeitos dos fármacos , Vírus da Raiva/imunologia , Vírus da Raiva/patogenicidade , Ratos , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de Sinais , Vacinas Sintéticas/biossíntese , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Vacinas de mRNARESUMO
Interferons (IFN) have been shown to alter lipid metabolism in immune and some non-hematopoietic cells and this affects host cell response to pathogens. In type 1 diabetes, IFNγ acts as a proinflammatory cytokine that, along with other cytokines, is released during pancreatic beta cell autoinflammation and contributes to immune response and beta cell dysfunction. The hypothesis tested herein is that IFN modifies beta cell lipid metabolism and this is associated with enhanced anti-viral response and beta cell stress. Treatment of INS-1 cells with IFNγ for 6 to 24 h led to a dynamic change in TAG and lipid droplet (LD) levels, with a decrease at 6 h and an increase at 24 h. The later accumulation of TAG was associated with increased de novo lipogenesis (DNL), and impaired mitochondrial fatty acid oxidation (FAO). Gene expression results suggested that IFNγ regulates lipolytic, lipogenic, LD and FAO genes in a temporal manner. The changes in lipid gene expression are dependent on the classical Janus kinase (JAK) pathway. Pretreatment with IFNγ robustly enhanced anti-viral gene expression induced by the viral mimetic polyinosinic: polycytidylic acid (PIC), and this potentiating effect of IFNγ was markedly attenuated by inhibitors of DNL. The IFNγ-induced accumulation of lipid, however, was insufficient to cause endoplasmic reticulum (ER) stress. These studies demonstrated a non-canonical effect of IFNγ in regulation of pancreatic beta cell lipid metabolism that is intimately linked with host cell defense and might alter cellular function early in the progression to type 1 diabetes.
Assuntos
Antivirais/imunologia , Células Secretoras de Insulina/imunologia , Interferon gama/imunologia , Metabolismo dos Lipídeos/imunologia , Animais , Células Cultivadas , Diabetes Mellitus Tipo 1/imunologia , Estresse do Retículo Endoplasmático/imunologia , Janus Quinases/imunologia , Poli I-C/imunologia , RatosRESUMO
The inflammasome machinery has recently been recognized as an emerging pillar of innate immunity. However, little is known regarding the interaction between the classical interferon (IFN) response and inflammasome activation in response to norovirus infection. We found that murine norovirus (MNV-1) infection induces the transcription of IL-1ß, a hallmark of inflammasome activation, which is further increased by inhibition of IFN response, but fails to trigger the release of mature IL-1ß. Interestingly, pharmacological inflammasome inhibitors do not affect viral replication, but slightly reverse the inflammasome activator lipopolysaccharide (LPS)-mediated inhibition of MNV replication. LPS efficiently stimulates the transcription of IFN-ß through NF-ĸB, which requires the transcription factors IRF3 and IRF7. This activates downstream antiviral IFN-stimulated genes (ISGs) via the JAK-STAT pathway. Moreover, inhibition of NF-ĸB and JAK-STAT signaling partially reverse LPS-mediated anti-MNV activity, suggesting additional antiviral mechanisms activated by NF-ĸB. This study reveals additional insight in host defense against MNV infection.
Assuntos
Antivirais/farmacologia , Infecções por Caliciviridae/imunologia , Janus Quinases/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , NF-kappa B/imunologia , Norovirus/efeitos dos fármacos , Fatores de Transcrição STAT/imunologia , Animais , Infecções por Caliciviridae/genética , Infecções por Caliciviridae/virologia , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Janus Quinases/genética , Macrófagos/virologia , Camundongos , NF-kappa B/genética , Norovirus/genética , Norovirus/fisiologia , Fatores de Transcrição STAT/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
The discovery of JAKs and STATs and their roles in cytokine and IFN action represented a significant basic advance and a new paradigm in cell signaling. This was quickly followed by discoveries pointing to their essential functions, including identification of JAK3 mutations as a cause of SCID. This and other findings predicted the use of therapeutically targeting JAKs as a new strategy for treating immune and inflammatory diseases. This now is a reality with seven approved jakinibs being used to treat multiple forms of arthritis, inflammatory bowel disease and myeloproliferative neoplasms, and numerous ongoing clinical trials in other settings. This story provides interesting insights into the process of translating basic discoveries and also reveals the need to return to basic work to fill gaps that now become apparent.
Assuntos
Janus Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Janus Quinases/imunologia , Janus Quinases/metabolismoRESUMO
Cytokines are involved in intestinal homeostasis and pathological processes associated with inflammatory bowel disease (IBD). The biological effects of cytokines, including several involved in the pathology of Crohn's disease and ulcerative colitis, occur as a result of receptor-mediated signalling through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) DNA-binding families of proteins. Although therapies targeting cytokines have revolutionized IBD therapy, they have historically targeted individual cytokines, and an unmet medical need exists for patients who do not respond to or lose response to these treatments. Several small-molecule inhibitors of JAKs that have the potential to affect multiple pro-inflammatory cytokine-dependent pathways are in clinical development for the treatment of IBD, with one agent, tofacitinib, already approved for ulcerative colitis and several other agents with demonstrated efficacy in early phase trials. This Review describes the current understanding of JAK-STAT signalling in intestinal homeostasis and disease and the rationale for targeting this pathway as a treatment for IBD. The available evidence for the efficacy, safety and pharmacokinetics of JAK inhibitors in IBD as well as the potential approaches to optimize treatment with these agents, such as localized delivery or combination therapy, are also discussed.
Assuntos
Citocinas/imunologia , Doenças Inflamatórias Intestinais/imunologia , Janus Quinases/imunologia , Fatores de Transcrição STAT/imunologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Intestinos/imunologia , Inibidores de Janus Quinases/uso terapêutico , Transdução de Sinais/imunologiaRESUMO
We have previously demonstrated that upregulation of Sonic hedgehog (SHH) expression in allergic airway epithelia essentially contributes to the goblet cell metaplasia and mucous hypersecretion. However, the mechanism underlying the upregulation of SHH expression remains completely unknown. In cultured human airway epithelial cells, IL-4/IL-13 but not IL-5 robustly induces the mRNA and protein expression of SHH and in turn activates SHH signaling by promoting the JAK/STAT6-controlling transcription of SHH gene. Moreover, intratracheal instillation of IL-4 and/or IL-13 robustly activates STAT6 and concomitantly upregulates SHH expression in mouse airway epithelia, whereas, in Club cell 10-kDa protein (CC10)-positive airway epithelial cells of children with asthma, activated STAT6 closely correlates with the increased expression of SHH and high activity of SHH signaling. Finally, intratracheal inhibition of STAT6 by AS-1517499 significantly diminished the allergen-induced upregulation of SHH expression, goblet cell phenotypes, and airway hyperresponsiveness, in an ovalbumin- or house dust mite-induced mouse model with allergic airway inflammation,. Together, upregulation of SHH expression by IL-4/IL-13-induced JAK/STAT6 signaling contributes to allergic airway epithelial remodeling, and this study thus provides insight into how morphogen signaling is coordinated with Th2 cytokine pathways to regulate tissue remodeling in chronic airway diseases.
Assuntos
Asma/genética , Proteínas Hedgehog/genética , Interleucina-13/genética , Interleucina-4/genética , Mucosa Respiratória/imunologia , Animais , Antiasmáticos/farmacologia , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/patologia , Linhagem Celular , Criança , Feminino , Regulação da Expressão Gênica , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/imunologia , Células Caliciformes/patologia , Proteínas Hedgehog/imunologia , Humanos , Interleucina-13/imunologia , Interleucina-13/farmacologia , Interleucina-4/imunologia , Interleucina-4/farmacologia , Interleucina-5/genética , Interleucina-5/imunologia , Janus Quinases/genética , Janus Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Cultura Primária de Células , Pirimidinas/farmacologia , Pyroglyphidae/química , Pyroglyphidae/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Fator de Transcrição STAT6/antagonistas & inibidores , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Transcrição Gênica , Uteroglobina/genética , Uteroglobina/imunologiaRESUMO
Enteric viruses including hepatitis E virus (HEV), human norovirus (HuNV), and rotavirus are causing global health issues. The host interferon (IFN) response constitutes the first-line defense against viral infections. Melanoma Differentiation-Associated protein 5 (MDA5) is an important cytoplasmic receptor sensing viral infection to trigger IFN production, and on the other hand it is also an IFN-stimulated gene (ISG). In this study, we investigated the effects and mode-of-action of MDA5 on the infection of enteric viruses. We found that MDA5 potently inhibited HEV, HuNV and rotavirus replication in multiple cell models. Overexpression of MDA5 induced transcription of important antiviral ISGs through IFN-like response, without triggering of functional IFN production. Interestingly, MDA5 activates the expression and phosphorylation of STAT1, which is a central component of the JAK-STAT cascade and a hallmark of antiviral IFN response. However, genetic silencing of STAT1 or pharmacological inhibition of the JAK-STAT cascade only partially attenuated the induction of ISG transcription and the antiviral function of MDA5. Thus, we have demonstrated that MDA5 effectively inhibits HEV, HuNV and rotavirus replication through provoking a non-canonical IFN-like response, which is partially dependent on JAK-STAT cascade.
Assuntos
Imunidade Inata , Helicase IFIH1 Induzida por Interferon/imunologia , Interferons/imunologia , Janus Quinases/imunologia , Fator de Transcrição STAT1/imunologia , Viroses/imunologia , Antivirais/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Vírus da Hepatite E , Humanos , Norovirus , Rotavirus , Transdução de Sinais , Replicação ViralRESUMO
BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. RESULTS: We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37). CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Herpes Zoster/epidemiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores de Janus Quinases/efeitos adversos , Psoríase/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/mortalidade , Azetidinas/efeitos adversos , Herpes Zoster/induzido quimicamente , Herpes Zoster/imunologia , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Incidência , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/mortalidade , Inibidores de Janus Quinases/administração & dosagem , Janus Quinases/antagonistas & inibidores , Janus Quinases/imunologia , Janus Quinases/metabolismo , Piperidinas/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Psoríase/imunologia , Psoríase/mortalidade , Purinas , Pirazóis , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/mortalidade , Sulfonamidas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Triazóis/efeitos adversosRESUMO
IBD treatment is undergoing a transformation with an expanding repertoire of drugs targeting different aspects of the immune response. Three novel classes of drugs have emerged in the past decade that target leukocyte trafficking to the gut (vedolizumab), neutralize key cytokines with antibodies (ustekinumab) and inhibit cytokine signalling pathways (tofacitinib). In advanced development are other drugs for IBD, including therapies targeting other cytokines such as IL-23 and IL-6. However, all agents tested so far are hampered by primary and secondary loss of response, so it is desirable to develop personalized strategies to identify which patients should be treated with which drugs. Stratification of patients with IBD by clinical parameters alone lacks sensitivity, and alternative modalities are now needed to deliver precision medicine in IBD. High-resolution profiling of immune response networks in individual patients is a promising approach and different technical platforms, including in vivo real-time molecular endoscopy, tissue transcriptomics and germline genetics, are promising tools to help predict responses to specific therapies. However, important challenges remain regarding the clinical utility of these technologies, including their scalability and accessibility. This Review focuses on unravelling some of the complexity of mucosal immune responses in IBD pathogenesis and how current and emerging analytical platforms might be harnessed to effectively stratify and individualise IBD therapy.
Assuntos
Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Medicina de Precisão , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Movimento Celular , Citocinas/imunologia , Endoscopia Gastrointestinal , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Microscopia Intravital , Janus Quinases/imunologia , Linfócitos/imunologia , Linfócitos/patologia , Microscopia Confocal , Prognóstico , Transdução de Sinais , Resultado do TratamentoRESUMO
BACKGROUND: Granuloma annulare (GA) is an inflammatory skin disorder. Localized GA is often self-resolving, but generalized GA is often recalcitrant to treatments. There are no targeted treatments for GA, largely due to lack of mechanistic understanding. Recently, tumor necrosis factor antagonism showed promise in GA, suggesting an underlying immune pathogenesis. OBJECTIVE: To elucidate the immune pathogenesis and identify potential therapeutic targets for GA. METHODS: Lesional and nonlesional skin biopsy samples were obtained from patients with GA and evaluated for a large array of inflammatory markers compared with inflammatory markers from normal skin of healthy individuals. RESULTS: We found differential expression of many inflammatory genes compared with normal skin. These genes were associated with T-helper (Th) cell type 1/innate immunity (tumor necrosis factor-α, interleukin [IL]-1ß, IL-12/23p40, signal transducer and activator of transcription 1, chemokine [C-X-C motif] ligand 9/10), Janus kinase signaling, and Th2 (IL-4, IL-31, chemokine (C-C motif) ligands 17 and 18; P < .05). Unexpectedly, IL-4 showed significant upregulation in GA lesional skin vs control skin (15,600-fold change). LIMITATIONS: Limited sample size. CONCLUSIONS: Our findings shed light on the inflammatory pathways of GA, supporting the notion that immune mechanisms could be driving disease, as suggested by the promising data of tumor necrosis factor-α inhibitors in GA. The significant Janus kinase and particularly Th2 signaling in GA advocates for the investigation of specific Janus kinase- and Th2- targeted drug therapy.
Assuntos
Granuloma Anular/imunologia , Janus Quinases/imunologia , Pele/imunologia , Células Th1/imunologia , Células Th2/imunologia , Biomarcadores/metabolismo , Biópsia , Feminino , Granuloma Anular/genética , Humanos , Imunidade Inata , Inflamação/genética , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Regulação para CimaRESUMO
Inflammation is a common feature of many neurodegenerative diseases. The treatment of stem cells as a therapeutic approach to repair damage in the central nervous system represents a valid alternative. In this study, using Next-Generation Sequencing (NGS) technology, we analyzed the transcriptomic profile of human Gingival Mesenchymal Stem Cells (hGMSCs) treated with Moringin [4-(α-l-ramanosyloxy)-benzyl isothiocyanate] (hGMSCs-MOR) or with Cannabidiol (hGMSCs-CBD) at dose of 0.5 or 5 µM, respectively. Moreover, we compared their transcriptomic profiles in order to evaluate analogies and differences in pro- and anti-inflammatory pathways. The hGMSCs-MOR selectively downregulate TNF-α signaling from the beginning, reducing the expression of TNF-α receptor while hGMSCs-CBD limit its activity after the process started. The treatment with CBD downregulates the pro-inflammatory pathway mediated by the IL-1 family, including its receptor while MOR is less efficient. Furthermore, both the treatments are efficient in the IL-6 signaling. In particular, CBD reduces the effect of the pro-inflammatory JAK/STAT pathway while MOR enhances the pro-survival PI3K/AKT/mTOR. In addition, both hGMSCs-MOR and hGMSCs-CBD improve the anti-inflammatory activity enhancing the TGF-ß pathway.