RESUMEN
The immune system is highly regulated but, when dysregulated, suboptimal protective or overly robust immune responses can lead to immune-mediated disorders. The genetic and molecular mechanisms of immune regulation are incompletely understood, impeding the development of more precise diagnostics and therapeutics for immune-mediated disorders. Recently, thousands of previously unrecognized noncanonical microprotein genes encoded by small open reading frames have been identified. Many of these microproteins perform critical functions, often in a cell- and context-specific manner. Several microproteins are now known to regulate immunity; however, the vast majority are uncharacterized. Therefore, illuminating what is often referred to as the "dark proteome," may present opportunities to tune immune responses more precisely. Here, we review noncanonical microprotein biology, highlight recently discovered examples regulating immunity, and discuss the potential and challenges of modulating dysregulated immune responses by targeting microproteins.
RESUMEN
Despite an ever-increasing appreciation of how protein-coding genes shape immune responses, the molecular underpinnings of immune regulation remain incompletely understood. This incomplete picture impedes the development of more precise therapeutics and diagnostics for immune-mediated diseases. Long noncoding RNAs (lncRNAs) are versatile cell- and context-specific regulators of gene expression and cellular function. The number of lncRNA genes rivals that of protein-coding genes; however, comparatively little is known about their function. Even though the functions of most lncRNA genes are unknown, multiple lncRNAs have recently emerged as important immune regulators. Therefore, further unlocking the role of lncRNAs in the mammalian immune system coupled with their tissue-specific expression might lead to more precise therapeutics and diagnostics for immune disorders in general.
Asunto(s)
Enfermedades del Sistema Inmune , ARN Largo no Codificante , Animales , Regulación de la Expresión Génica , Humanos , Sistema Inmunológico/metabolismo , Mamíferos , ARN Largo no Codificante/genéticaRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for high-risk hematologic disorders. There are multiple immune-mediated complications following allo-HSCT that are prevented and/or treated by immunosuppressive agents. Principal among these immune-mediated complications is acute graft-versus-host disease (aGVHD), which occurs when the new donor immune system targets host tissue antigens. The immunobiology of aGVHD is complex and involves all aspects of the immune system. Due to the risk of aGVHD, immunosuppressive aGVHD prophylaxis is required for nearly all allogeneic HSCT recipients. Despite prophylaxis, aGVHD remains a major cause of nonrelapse mortality. Here, we discuss the clinical features of aGVHD, the immunobiology of aGVHD, the immunosuppressive therapies used to prevent and treat aGVHD, how to mitigate the side effects of these immunosuppressive therapies, and what additional immune-mediated post-allo-HSCT complications are also treated with immunosuppression.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Terapia de InmunosupresiónRESUMEN
Immune checkpoint inhibitors (ICIs) have been a transformational advance in cancer therapy in the past decade. However, ICIs can produce immune-related adverse effects (irAEs), which can lead to both morbidity and premature termination of therapy. Recent studies suggest that the gut microbiota and its metabolites affect ICI efficacy and toxicity. Herein, we review such evidence in the context of ICI-induced colitis. In particular, the short-chain fatty acid butyrate, a microbial metabolite, has known protective effects on the intestine. We discuss how the use of dietary prebiotics, which can be metabolized by bacteria to produce butyrate, can be an intriguing new investigational approach to prevent ICI-associated colitis and lead to improved patient outcomes.
Asunto(s)
Colitis/prevención & control , Microbioma Gastrointestinal/inmunología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/tratamiento farmacológico , Prebióticos/administración & dosificación , Animales , Butiratos/metabolismo , Colitis/inducido químicamente , Colitis/inmunología , Colitis/microbiología , Modelos Animales de Enfermedad , Humanos , Ratones , Neoplasias/inmunologíaRESUMEN
Allogeneic hematopoietic cell transplantation (allo-HCT) through its graft-versus-tumor (GVT) effects is a curative therapy against many hematological malignancies. However, GVT is linked to harmful graft-versus-host disease (GVHD) after allo-HCT. Both GVT and GVHD require allogeneic T cell responses, which is an energetically costly process that causes oxidative stress. Sirtuin 3 (SIRT3), a mitochondrial histone deacetylase (HDAC), plays an important role in cellular processes through inhibition of reactive oxygen species (ROS). Nonmitochondrial class of HDACs regulate T cell responses, but the role of mitochondrial HDACs, specifically SIRT3, on donor T cell responses after allo-HCT remains unknown. In this study, we report that SIRT3-deficient (SIRT3-/-) donor T cells cause reduced GVHD severity in multiple clinically relevant murine models. The GVHD protective effect of allogeneic SIRT3-/- T cells was associated with a reduction in their activation, reduced CXCR3 expression, and no significant impact on cytokine secretion or cytotoxic functions. Intriguingly, the GVHD protective effect of SIRT3-/- T cells was associated with a reduction in ROS production, which is contrary to the effect of SIRT3 deficiency on ROS production in other cells/tissues and likely a consequence of their deficient activation. Notably, the reduction in GVHD in the gastrointestinal tract was not associated with a substantial reduction in the GVT effect. Collectively, these data reveal that SIRT3 activity promotes allogeneic donor T cell responses and ROS production without altering T cell cytokine or cytolytic functions and identify SIRT3 as a novel target on donor T cells to improve outcomes after allo-HCT.
Asunto(s)
Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/metabolismo , Efecto Injerto vs Tumor , Trasplante de Células Madre Hematopoyéticas , Mitocondrias/metabolismo , Sirtuina 3/metabolismo , Linfocitos T/inmunología , Animales , Células Cultivadas , Humanos , Isoantígenos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Sirtuina 3/genética , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Professional antigen-presenting cells (APCs) are important modulators of acute graft-versus-host disease (GVHD). Although dendritic cells (DCs) are the most potent APC subset, other myeloid cells, especially macrophages (MFs) and neutrophils, recently have been shown to play a role in the severity of GVHD. The critical molecular mechanisms that determine the functions of myeloid cells in GVHD are unclear, however. Signal transducer and activator of transcription 3 (STAT3) is a master transcription factor that plays a crucial role in regulating immunity, but its role in MF biology and in acute GVHD remains unknown. To determine the impact of myeloid cell-specific expression of STAT3 on the severity of acute GVHD, we used myeloid cell-specific STAT3-deficient LysM-Cre/STAT3fl/- animals as recipients and donors in well-characterized experimental models of acute GVHD. We found that reduced expression of STAT3 in myeloid cells from the hosts, but not the donors, increased inflammation, increased donor T cell activation, and exacerbated GVHD. Our data demonstrate that STAT3 in host myeloid cells, such as MFs, dampens acute GVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Células Mieloides/metabolismo , Factor de Transcripción STAT3/genética , Animales , Ratones , Ratones Endogámicos BALB C , Factor de Transcripción STAT3/biosíntesis , Receptores de Trasplantes , Trasplante HomólogoRESUMEN
Cell-intrinsic innate immune responses mediated by the transcription factor interferon regulatory factor 3 (IRF-3) are often vital for early pathogen control, and effective responses in neurons may be crucial to prevent the irreversible loss of these critical central nervous system cells after infection with neurotropic pathogens. To investigate this hypothesis, we used targeted molecular and genetic approaches with cultured neurons to study cell-intrinsic host defense pathways primarily using the neurotropic alphavirus western equine encephalitis virus (WEEV). We found that WEEV activated IRF-3-mediated neuronal innate immune pathways in a replication-dependent manner, and abrogation of IRF-3 function enhanced virus-mediated injury by WEEV and the unrelated flavivirus St. Louis encephalitis virus. Furthermore, IRF-3-dependent neuronal protection from virus-mediated cytopathology occurred independently of autocrine or paracrine type I interferon activity. Despite being partially controlled by IRF-3-dependent signals, WEEV also disrupted antiviral responses by inhibiting pattern recognition receptor pathways. This antagonist activity was mapped to the WEEV capsid gene, which disrupted signal transduction downstream of IRF-3 activation and was independent of capsid-mediated inhibition of host macromolecular synthesis. Overall, these results indicate that innate immune pathways have important cytoprotective activity in neurons and contribute to limiting injury associated with infection by neurotropic arboviruses.
Asunto(s)
Arbovirus/inmunología , Proteínas de la Cápside/metabolismo , Virus de la Encefalitis Equina del Oeste/inmunología , Virus de la Encefalitis Equina del Oeste/patogenicidad , Factor 3 Regulador del Interferón/inmunología , Neuronas/virología , Animales , Línea Celular , Efecto Citopatogénico Viral/inmunología , Virus de la Encefalitis de San Luis/crecimiento & desarrollo , Virus de la Encefalitis Equina del Oeste/crecimiento & desarrollo , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
Innate immune pathways are early defense responses important for the immediate control and eventual clearance of many pathogens, where signaling is initiated via pattern recognition receptor (PRR)-mediated events that occur in a ligand- and cell-type specific manner. Within CNS neurons, innate immune pathways are likely crucial to control pathogens that target these essential yet virtually irreplaceable cells. However, relatively little is known about the induction and regulation of neuronal PRR signaling. In this report, we used human neuronal cell lines and primary rat neuronal cultures to examine PRR expression and function. We found that several innate immune receptor ligands, including Sendai virus, the dsRNA mimetic polyinosinic-polycytidylic acid, and LPS all activated differentiation-dependent neuronal innate immune pathways. Functional genetic analyses revealed that IFN regulatory factor 3-mediated pathways that resulted in IFN-beta transcriptional upregulation were activated in cultured human neuronal cells by the PRRs TLR3, MDA5, or RIG-I in a ligand-specific manner. Furthermore, genome-wide transcriptional array and targeted genetic and pharmacologic analyses identified PI3K signaling as crucial for the induction of innate immune pathways in neurons. These results indicate that human neuronal cells possess specific and functional PRR pathways essential for the effective induction of innate immune responses, and suggest that neurons can play an active role in defense against neurotropic pathogens.
Asunto(s)
Inmunidad Innata , Neuronas/inmunología , Fosfatidilinositol 3-Quinasas/inmunología , Transducción de Señal/inmunología , Receptores Toll-Like/inmunología , Animales , Línea Celular , Citoplasma/inmunología , Citoplasma/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Immunoblotting , Neuronas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Neurotropic alphaviruses such as western, eastern, and Venezuelan equine encephalitis viruses cause serious and potentially fatal central nervous system infections in humans and are high-priority potential bioterrorism agents. There are currently no widely available vaccines or licensed therapies for these virulent pathogens. To identify potential novel antiviral drugs, we developed a cell-based assay with a western equine encephalitis virus replicon that expresses a luciferase reporter gene and screened a small molecule diversity library of 51,028 compounds. We identified and validated a thieno[3,2-b]pyrrole compound with a half maximal inhibitory concentration of <10 micromol/L, a selectivity index>20, and potent activity against live virus in cultured neuronal cells. Furthermore, a structure-activity relationship analysis with 20 related compounds identified several with enhanced activity profiles, including 6 with submicromolar half maximal inhibitory concentrations. In conclusion, we have identified a novel class of promising inhibitors with potent activity against virulent neurotropic alphaviruses.
Asunto(s)
Alphavirus/efectos de los fármacos , Antivirales/farmacología , Pirroles/farmacología , Alphavirus/fisiología , Animales , Antivirales/química , Bioensayo , Línea Celular , Chlorocebus aethiops , Cricetinae , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirroles/química , Relación Estructura-Actividad , Proteínas Reguladoras y Accesorias Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Innate cell-autonomous antiviral responses are essential first lines of defense against central nervous system infections but may also contribute to neuropathogenesis. We investigated the relationships between innate immunity and neuronal differentiation using an in vitro culture system with human cell lines to analyze cellular responses to the neurotropic alphavirus western equine encephalitis virus. Human neuronal cells displayed a maturation-dependent reduction in virus-induced cytopathology that was independent of autocrine interferon alpha or beta activity. In addition, maturation was associated with enhanced responsiveness to exogenous stimuli, such that differentiated neurons required five- to ten-fold less type I interferon to suppress viral replication or virus-induced cytopathology compared to immature cells, although this enhanced responsiveness extended to only a subset of unique type I interferons. These results demonstrate that maturation-dependent changes in human neuronal cells may be key determinants in the innate immune response to infections with neurotropic alphaviruses.