RESUMO
How mis-regulated chromatin directly impacts human immune disorders is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing epigenetic "reader," and SP140 loss-of-function mutations associate with Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the relevance of these mutations and mechanisms underlying SP140-driven pathogenicity remains unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOPs) that maintains heterochromatin and macrophage fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, de-repression of developmentally silenced genes, and ultimately defective microbe-inducible macrophage transcriptional programs and bacterial killing that drive intestinal pathology. Pharmacological inhibition of TOP1/2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1/2 inhibitors in Sp140-/- mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a TOP repressor and reveal repurposing of TOP inhibition to reverse immune diseases driven by SP140 loss.
Assuntos
Doença de Crohn , Animais , Humanos , Camundongos , Antígenos Nucleares , Doença de Crohn/genética , Doença de Crohn/patologia , Epigênese Genética , Regulação da Expressão Gênica , Macrófagos/patologia , Proteômica , Fatores de TranscriçãoAssuntos
Imunidade Adaptativa , Tolerância Imunológica , Imunidade Inata , Memória Imunológica , Imunidade Adaptativa/imunologia , Animais , Vacina BCG/imunologia , Diferenciação Celular , Humanos , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , VacinaçãoRESUMO
Detailed understanding of the signaling intermediates that confer the sensing of intracellular viral nucleic acids for induction of type I interferons is critical for strategies to curtail viral mechanisms that impede innate immune defenses. Here we show that the activation of the microtubule-associated guanine nucleotide exchange factor GEF-H1, encoded by Arhgef2, is essential for sensing of foreign RNA by RIG-I-like receptors. Activation of GEF-H1 controls RIG-I-dependent and Mda5-dependent phosphorylation of IRF3 and induction of IFN-ß expression in macrophages. Generation of Arhgef2(-/-) mice revealed a pronounced signaling defect that prevented antiviral host responses to encephalomyocarditis virus and influenza A virus. Microtubule networks sequester GEF-H1 that upon activation is released to enable antiviral signaling by intracellular nucleic acid detection pathways.
Assuntos
Imunidade Inata/imunologia , Microtúbulos/imunologia , RNA Viral/imunologia , Fatores de Troca de Nucleotídeo Guanina Rho/imunologia , Transdução de Sinais/imunologia , Animais , Células COS , Chlorocebus aethiops , Proteína DEAD-box 58 , RNA Helicases DEAD-box/imunologia , RNA Helicases DEAD-box/metabolismo , Expressão Gênica/imunologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Imunidade Inata/genética , Immunoblotting , Vírus da Influenza A/genética , Fator Regulador 3 de Interferon/imunologia , Fator Regulador 3 de Interferon/metabolismo , Helicase IFIH1 Induzida por Interferon , Interferon beta/genética , Interferon beta/imunologia , Interferon beta/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Microtúbulos/metabolismo , Fosforilação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Transdução de Sinais/genéticaRESUMO
Dendritic cells (DCs), critical antigen-presenting cells for immune control, normally derive from bone marrow precursors distinct from monocytes. It is not yet established if the large reservoir of monocytes can develop into cells with critical features of DCs in vivo. We now show that fully differentiated monocyte-derived DCs (Mo-DCs) develop in mice and DC-SIGN/CD209a marks the cells. Mo-DCs are recruited from blood monocytes into lymph nodes by lipopolysaccharide and live or dead gram-negative bacteria. Mobilization requires TLR4 and its CD14 coreceptor and Trif. When tested for antigen-presenting function, Mo-DCs are as active as classical DCs, including cross-presentation of proteins and live gram-negative bacteria on MHC I in vivo. Fully differentiated Mo-DCs acquire DC morphology and localize to T cell areas via L-selectin and CCR7. Thus the blood monocyte reservoir becomes the dominant presenting cell in response to select microbes, yielding DC-SIGN(+) cells with critical functions of DCs.
Assuntos
Moléculas de Adesão Celular/metabolismo , Diferenciação Celular , Células Dendríticas/citologia , Escherichia coli/imunologia , Lectinas Tipo C/metabolismo , Monócitos/citologia , Receptores de Superfície Celular/metabolismo , Animais , Apresentação de Antígeno , Moléculas de Adesão Celular/imunologia , Células Dendríticas/imunologia , Selectina L/imunologia , Lectinas Tipo C/imunologia , Receptores de Lipopolissacarídeos/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Receptores CCR7/imunologia , Receptores de Superfície Celular/imunologia , Linfócitos T/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologiaRESUMO
Chromatin 'readers' are central interpreters of the epigenome that facilitate cell-specific transcriptional programs and are therapeutic targets in cancer and inflammation. The Speckled Protein (SP) family of chromatin 'readers' in humans consists of SP100, SP110, SP140, and SP140L. SPs possess functional domains (SAND, PHD, bromodomain) that dock to DNA or post-translationally modified histones and a caspase activation and recruitment domain (CARD) to promote multimerization. Mutations within immune expressed SPs associate with numerous immunological diseases including Crohn's disease, multiple sclerosis, chronic lymphocytic leukemia, veno-occlusive disease with immunodeficiency, as well as Mycobacterium tuberculosis infection, underscoring their importance in immune regulation. In this review, we posit that SPs are central chromatin regulators of gene silencing that establish immune cell identity and function.
Assuntos
Antígenos Nucleares , Cromatina , Antígenos Nucleares/genética , Antígenos Nucleares/imunologia , Cromatina/imunologia , Inativação Gênica , Histonas/genética , Histonas/metabolismo , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Mutação , Domínios Proteicos/genéticaRESUMO
Viral infection is commonly associated with virus-driven hijacking of host proteins. Here we describe a novel mechanism by which influenza virus affects host cells through the interaction of influenza non-structural protein 1 (NS1) with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 subtype possesses a histone-like sequence (histone mimic) that is used by the virus to target the human PAF1 transcription elongation complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C depends on the NS1 histone mimic and results in suppression of hPAF1C-mediated transcriptional elongation. Furthermore, human PAF1 has a crucial role in the antiviral response. Loss of hPAF1C binding by NS1 attenuates influenza infection, whereas hPAF1C deficiency reduces antiviral gene expression and renders cells more susceptible to viruses. We propose that the histone mimic in NS1 enables the influenza virus to affect inducible gene expression selectively, thus contributing to suppression of the antiviral response.
Assuntos
Regulação da Expressão Gênica , Histonas/metabolismo , Vírus da Influenza A Subtipo H3N2/metabolismo , Influenza Humana/genética , Influenza Humana/imunologia , Mimetismo Molecular , Proteínas não Estruturais Virais/metabolismo , Sequência de Aminoácidos , Regulação da Expressão Gênica/imunologia , Histonas/química , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/patologia , Influenza Humana/virologia , Dados de Sequência Molecular , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Ligação Proteica , Fatores de Transcrição , Transcrição Gênica/imunologia , Proteínas não Estruturais Virais/químicaRESUMO
Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.
Assuntos
Anti-Inflamatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamação , Macrófagos/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Benzodiazepinas , Células Cultivadas , Epigenômica , Estudo de Associação Genômica Ampla , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Estimativa de Kaplan-Meier , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Infecções por Salmonella/tratamento farmacológico , Infecções por Salmonella/imunologia , Infecções por Salmonella/fisiopatologia , Infecções por Salmonella/prevenção & controle , Salmonella typhimurium , Sepse/tratamento farmacológico , Sepse/prevenção & controle , Choque Séptico/tratamento farmacológico , Choque Séptico/prevenção & controleRESUMO
The interaction of innate immune cells with pathogens leads to changes in gene expression that elicit our body's first line of defense against infection. Although signaling pathways and transcription factors have a central role, it is becoming increasingly clear that epigenetic factors, in the form of DNA or histone modifications, as well as noncoding RNAs, are critical for generating the necessary cell lineage as well as context-specific gene expression in diverse innate immune cell types. Much of the epigenetic landscape is set during cellular differentiation; however, pathogens and other environmental triggers also induce changes in histone modifications that can either promote tolerance or 'train' innate immune cells for a more robust antigen-independent secondary response. Here we review the important contribution of epigenetic factors to the initiation, maintenance and training of innate immune responses. In addition, we explore how pathogens have hijacked these mechanisms for their benefit and the potential of small molecules targeting chromatin machinery as a way to boost or subdue the innate immune response in disease.
Assuntos
Epigênese Genética , Interações Hospedeiro-Patógeno/genética , Imunidade Inata/genética , RNA não Traduzido/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Microambiente Celular , Metilação de DNA , Regulação da Expressão Gênica/imunologia , Histonas/metabolismo , Humanos , Imunomodulação , Processamento de Proteína Pós-Traducional , Transdução de Sinais/imunologiaRESUMO
Immunoglobulin G (IgG) antibodies in the form of high-dose intravenous immunoglobulin (IVIG) exert immunomodulatory activity and are used in this capacity to treat inflammatory and autoimmune diseases. Reductionist approaches have revealed that terminal sialylation of the single asparagine-linked (N-linked) glycan at position 297 of the IgG1 Fc bestows antiinflammatory activity, which can be recapitulated by introduction of an F241A point mutation in the IgG1 Fc (FcF241A). Here, we examined the antiinflammatory activity of CHO-K1 cell-produced FcF241A in vivo in models of autoimmune inflammation and found it to be independent of sialylation. Intriguingly, sialylation markedly improved the half-life and bioavailability of FcF241A via impaired interaction with the asialoglycoprotein receptor ASGPR. Further, FcF241A suppressed inflammation through the same molecular pathways as IVIG and sialylated IgG1 Fc and required the C-type lectin SIGN-R1 in vivo. This contrasted with FcAbdeg (efgartigimod), an engineered IgG1 Fc with enhanced neonatal Fc receptor (FcRn) binding, which reduced total serum IgG concentrations, independent of SIGN-R1. When coadministered, FcF241A and FcAbdeg exhibited combinatorial antiinflammatory activity. Together, these results demonstrated that the antiinflammatory activity of FcF241A requires SIGN-R1, similarly to that of high-dose IVIG and sialylated IgG1, and can be used in combination with other antiinflammatory therapeutics that rely on divergent pathways, including FcAbdeg.
Assuntos
Imunoglobulina G , Imunoglobulinas Intravenosas , Recém-Nascido , Humanos , Imunoglobulina G/genética , Imunoglobulina G/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/farmacologia , Inflamação/genética , Inflamação/tratamento farmacológico , Receptores Fc/genética , GlicosilaçãoRESUMO
Reversible genomic DNA inversions control the expression of numerous gut bacterial molecules, but how this impacts disease remains uncertain. By analyzing metagenomic samples from inflammatory bowel disease (IBD) cohorts, we identified multiple invertible regions where a particular orientation correlated with disease. These include the promoter of polysaccharide A (PSA) of Bacteroides fragilis, which induces regulatory T cells (Tregs) and ameliorates experimental colitis. The PSA promoter was mostly oriented "OFF" in IBD patients, which correlated with increased B. fragilis-associated bacteriophages. Similarly, in mice colonized with a healthy human microbiota and B. fragilis, induction of colitis caused a decline of PSA in the "ON" orientation that reversed as inflammation resolved. Monocolonization of mice with B. fragilis revealed that bacteriophage infection increased the frequency of PSA in the "OFF" orientation, causing reduced PSA expression and decreased Treg cells. Altogether, we reveal dynamic bacterial phase variations driven by bacteriophages and host inflammation, signifying bacterial functional plasticity during disease.
Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Humanos , Animais , Camundongos , Doenças Inflamatórias Intestinais/microbiologia , Inflamação , DNARESUMO
Canonical animal microRNAs (miRNAs) are generated by sequential cleavage of precursor substrates by the Drosha and Dicer RNase III enzymes. Several variant pathways exploit other RNA metabolic activities to generate functional miRNAs. However, all of these pathways culminate in Dicer cleavage, suggesting that this is a unifying feature of miRNA biogenesis. Here, we show that maturation of miR-451, a functional miRNA that is perfectly conserved among vertebrates, is independent of Dicer. Instead, structure-function and knockdown studies indicate that Drosha generates a short pre-mir-451 hairpin that is directly cleaved by Ago2 and followed by resection of its 3' terminus. We provide stringent evidence for this model by showing that Dicer knockout cells can generate mature miR-451 but not other miRNAs, whereas Ago2 knockout cells reconstituted with wild-type Ago2, but not Slicer-deficient Ago2, can process miR-451. Finally, we show that the mir-451 backbone is amenable to reprogramming, permitting vector-driven expression of diverse functional miRNAs in the absence of Dicer. Beyond the demonstration of an alternative strategy to direct gene silencing, these observations open the way for transgenic rescue of Dicer conditional knockouts.
Assuntos
Fator de Iniciação 2 em Eucariotos/metabolismo , MicroRNAs/biossíntese , Animais , Proteínas Argonautas , Sequência de Bases , Sequência Conservada , RNA Helicases DEAD-box/metabolismo , Primers do DNA/genética , Endorribonucleases/metabolismo , Fator de Iniciação 2 em Eucariotos/deficiência , Fator de Iniciação 2 em Eucariotos/genética , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/antagonistas & inibidores , MicroRNAs/química , MicroRNAs/genética , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Conformação de Ácido Nucleico , RNA Interferente Pequeno/genética , Ribonuclease III/metabolismo , Homologia de Sequência do Ácido NucleicoRESUMO
Neutrophil extracellular traps (NETs) not only counteract bacterial and fungal pathogens but can also promote thrombosis, autoimmunity, and sterile inflammation. The presence of citrullinated histones, generated by the peptidylarginine deiminase 4 (PAD4), is synonymous with NETosis and is considered independent of apoptosis. Mitochondrial- and death receptor-mediated apoptosis promote gasdermin E (GSDME)-dependent calcium mobilization and membrane permeabilization leading to histone H3 citrullination (H3Cit), nuclear DNA extrusion, and cytoplast formation. H3Cit is concentrated at the promoter in bone marrow neutrophils and redistributes in a coordinated process from promoter to intergenic and intronic regions during apoptosis. Loss of GSDME prevents nuclear and plasma membrane disruption of apoptotic neutrophils but prolongs early apoptosis-induced cellular changes to the chromatin and cytoplasmic granules. Apoptotic signaling engages PAD4 in neutrophils, establishing a cellular state that is primed for NETosis, but that occurs only upon membrane disruption by GSDME, thereby redefining the end of life for neutrophils.
Assuntos
Armadilhas Extracelulares , Neutrófilos , Neutrófilos/metabolismo , Desiminases de Arginina em Proteínas/genética , Desiminases de Arginina em Proteínas/metabolismo , Proteína-Arginina Desiminase do Tipo 4/genética , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Armadilhas Extracelulares/genética , Armadilhas Extracelulares/metabolismo , Histonas/metabolismo , Epigênese GenéticaRESUMO
A hallmark of the innate immune system is its ability to rapidly initiate short-lived or sustained transcriptional programs in a cell-specific and pathogen-specific manner that is dependent on dynamic chromatin states. Much of the epigenetic landscape is set during cellular differentiation; however, pathogens and other environmental cues also induce changes in chromatin that can either promote tolerance or 'train' innate immune cells for amplified secondary responses. We review chromatin processes that enable innate immune cell differentiation and functional transcriptional responses in naive or experienced cells, in concert with signal transduction and cellular metabolic shifts. We discuss how immune chromatin mechanisms are maladapted in disease and novel therapeutic approaches for cellular reprogramming.
Assuntos
Epigênese Genética , Imunidade Inata , Cromatina/genética , Epigenômica , Humanos , Sistema ImunitárioRESUMO
Inflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Speckled Protein 140 (SP140) is an immune-restricted chromatin "reader" that is associated with Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the disease-causing mechanisms of SP140 remain undefined. Here, we identify an immune-intrinsic role for SP140 in regulating phagocytic defense responses to prevent the expansion of inflammatory bacteria. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis that was transmissible upon cohousing and ameliorated with antibiotics. Loss of SP140 results in blooms of Proteobacteria, including Helicobacter in Sp140-/- mice and Enterobacteriaceae in humans bearing the CD-associated SP140 loss-of-function variant. Phagocytes from patients with the SP140 loss-of-function variant and Sp140-/- mice exhibited altered antimicrobial defense programs required for control of pathobionts. Thus, mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by microbiota.
Assuntos
Doença de Crohn , Doenças Inflamatórias Intestinais , Microbiota , Animais , Antibacterianos , Antígenos Nucleares/genética , Cromatina , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Camundongos , Fatores de Transcrição/genéticaRESUMO
Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses and bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn's disease colon resection viromes provoked inflammation, which was successfully dampened by non-IBD viromes. The IBD colon tissue virome was perturbed, including an increase in the enterovirus B species of eukaryotic picornaviruses, not previously detected in fecal virome studies. Mice humanized with non-IBD colon tissue viromes were protected from intestinal inflammation, whereas IBD virome mice exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD patient-derived intestinal epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed to viromes. Our results demonstrate that innate recognition of IBD or non-IBD human viromes autonomously influences intestinal homeostasis and disease phenotypes. Thus, perturbations in the intestinal virome, or an altered ability to sense the virome due to genetic variation, contribute to the induction of IBD. Harnessing the virome may offer therapeutic and biomarker potential.
Assuntos
Enterovirus , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Vírus , Animais , Humanos , Imunomodulação , Inflamação , Camundongos , FenótipoRESUMO
A sleepless night may feel awful in its aftermath, but sleep's revitalizing powers are substantial, perpetuating the idea that convalescent sleep is a consequence-free physiological reset. Although recent studies have shown that catch-up sleep insufficiently neutralizes the negative effects of sleep debt, the mechanisms that control prolonged effects of sleep disruption are not understood. Here, we show that sleep interruption restructures the epigenome of hematopoietic stem and progenitor cells (HSPCs) and increases their proliferation, thus reducing hematopoietic clonal diversity through accelerated genetic drift. Sleep fragmentation exerts a lasting influence on the HSPC epigenome, skewing commitment toward a myeloid fate and priming cells for exaggerated inflammatory bursts. Combining hematopoietic clonal tracking with mathematical modeling, we infer that sleep preserves clonal diversity by limiting neutral drift. In humans, sleep restriction alters the HSPC epigenome and activates hematopoiesis. These findings show that sleep slows decay of the hematopoietic system by calibrating the hematopoietic epigenome, constraining inflammatory output, and maintaining clonal diversity.
Assuntos
Hematopoese , Células-Tronco Hematopoéticas , Células Cultivadas , Hematopoese/genética , Células-Tronco Hematopoéticas/fisiologia , Humanos , Sono/genéticaRESUMO
SARS-CoV-2 has mutually illuminated our collective knowledge and knowledge gaps, particularly in antiviral defense and therapeutic strategies. A recent study in Science (Poirier et al., 2021) uncovers an ancient antiviral mechanism that mammals utilize to suppress viruses, including SARS-CoV-2 and Zika virus, that could have broad implications for therapeutic strategies.
Assuntos
Proteínas Argonautas/metabolismo , COVID-19/prevenção & controle , Interferons/imunologia , Interferência de RNA/fisiologia , Ribonuclease III/metabolismo , Infecção por Zika virus/prevenção & controle , Animais , Linhagem Celular , Células HEK293 , Humanos , RNA Interferente Pequeno/genética , RNA Viral/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Replicação Viral , Zika virus/genética , Zika virus/imunologiaRESUMO
Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine phosphatases, many of which dephosphorylate threonine and tyrosine residues on mitogen-activated protein kinases (MAPKs), and hence are also referred to as MAPK phosphatases (MKPs). The regulated expression and activity of DUSP family members in different cells and tissues controls MAPK intensity and duration to determine the type of physiological response. For immune cells, DUSPs regulate responses in both positive and negative ways, and DUSP-deficient mice have been used to identify individual DUSPs as key regulators of immune responses. From a drug discovery perspective, DUSP family members are promising drug targets for manipulating MAPK-dependent immune responses in a cell-type and disease-context-dependent manner, to either boost or subdue immune responses in cancers, infectious diseases or inflammatory disorders.
Assuntos
Imunidade/fisiologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Monoéster Fosfórico Hidrolases/fisiologia , Transdução de Sinais/fisiologia , Animais , Humanos , Proteínas Tirosina Fosfatases/fisiologia , Especificidade por SubstratoRESUMO
Environmental triggers in the context of genetic susceptibility drive phenotypes of complex immune disorders such as Inflammatory bowel disease (IBD). One such trigger of IBD is perturbations in enteric commensal bacteria, fungi or viruses that shape both immune and neuronal state. The epigenome acts as an interface between microbiota and context-specific gene expression and is thus emerging as a third key contributor to IBD. Here we review evidence that the host epigenome plays a significant role in orchestrating the bidirectional crosstalk between mammals and their commensal microorganisms. We discuss disruption of chromatin regulatory regions and epigenetic enzyme mutants as a causative factor in IBD patients and mouse models of intestinal inflammation and consider the possible translation of this knowledge. Furthermore, we present emerging insights into the intricate connection between the microbiome and epigenetic enzyme activity via host or bacterial metabolites and how these interactions fine-tune the microorganism-host relationship.