RESUMEN
We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the Φ11 prophage (mΦ11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present report shows how prophage mΦ11 exerts its effect on virulence for skin infection without encoding a known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an mΦ11-encoded adenine methyltransferase (designated pamA). pamA increased expression of fibronectin-binding protein A (fnbA; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA. Thus, fnbA is a pamA-specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA's role in biofilm formation. Collectively, these data reveal a novel mechanism-epigenetic regulation of staphylococcal gene expression-by which phage can regulate virulence to drive adaptive leaps by S. aureus.
RESUMEN
Autoantibodies to chromatin and dsDNA are a hallmark of systemic lupus erythematosus (SLE). In a mouse model of monogenic human SLE caused by DNASE1L3 deficiency, the anti-DNA response is dependent on endosomal nucleic acid-sensing TLRs TLR7 and TLR9. In this study, we report that this response also required TLR2, a surface receptor for microbial products that is primarily expressed on myeloid cells. Cell transfers into lymphopenic DNASE1L3-deficient mice showed that TLR2 was required for anti-DNA Ab production by lymphocytes. TLR2 was detectably expressed on B cells and facilitated the production of IL-6 by B cells activated in the presence of microbial products. Accordingly, treatment with broad-spectrum antibiotics or Ab-mediated blockade of IL-6 delayed the anti-DNA response in DNASE1L3-deficient mice. These studies reveal an unexpected B cell-intrinsic role of TLR2 in systemic autoreactivity to DNA, and they suggest that microbial products may synergize with self-DNA in the activation of autoreactive B cells in SLE.
Asunto(s)
Lupus Eritematoso Sistémico , Receptor Toll-Like 2 , Ratones , Animales , Humanos , Interleucina-6 , Linfocitos B , Autoanticuerpos , Anticuerpos Antinucleares , ADNRESUMEN
Extracellular DNase DNASE1L3 maintains tolerance to self-DNA in humans and mice, whereas the role of its homolog DNASE1 remains controversial, and the overall function of secreted DNases in immunity is unclear. We report that deletion of murine DNASE1 neither caused autoreactivity in isolation nor exacerbated lupus-like disease in DNASE1L3-deficient mice. However, combined deficiency of DNASE1 and DNASE1L3 rendered mice susceptible to bloodstream infection with Staphylococcus aureus. DNASE1/DNASE1L3 double-deficient mice mounted a normal innate response to S. aureus and did not accumulate neutrophil extracellular traps (NETs). However, their kidneys manifested severe pathology, increased bacterial burden, and biofilm-like bacterial lesions that contained bacterial DNA and excluded neutrophils. Furthermore, systemic administration of recombinant DNASE1 protein during S. aureus infection rescued the mortality of DNase-deficient mice and ameliorated the disease in wild-type mice. Thus, DNASE1 and DNASE1L3 jointly facilitate the control of bacterial infection by digesting extracellular microbial DNA in biofilms, suggesting the original evolutionary function of secreted DNases as antimicrobial agents.
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Biopelículas , Endodesoxirribonucleasas , Sepsis , Infecciones Estafilocócicas , Animales , Ratones , Desoxirribonucleasa I/genética , Desoxirribonucleasa I/metabolismo , Desoxirribonucleasas/metabolismo , ADN/metabolismo , Endodesoxirribonucleasas/metabolismo , Trampas Extracelulares/metabolismo , Mamíferos/genética , Mamíferos/metabolismo , Infecciones Estafilocócicas/prevención & control , Staphylococcus aureus/metabolismoRESUMEN
Recent studies have identified NF-κB1 as a new disease susceptibility gene for psoriasis. Although accumulating evidence has shown the importance of NF-κB signaling in various cell types in the pathogenesis of psoriasis, it remains unclear how NF-κB1 contributes to the pathogenesis of psoriasis. In this study, we examined psoriasis-like skin diseases induced by topical administration of imiquimod in Nf-κb1âdeficient (Nf-κb1-/-) mice and littermate wild-type (WT) mice. Compared with WT mice, Nf-κb1-/- mice exhibited attenuated skin inflammation. The numbers of Vγ4+Vδ4+γδT17 cells, which cause skin inflammation in this model, were significantly reduced in the skin and draining lymph nodes in imiquimod-treated Nf-κb1-/- mice. Nf-κb1 is preferentially phosphorylated in Vγ4+Vδ4+γδT17 cells in WT mice. In vitro proliferation of Vγ4+Vδ4+γδT17 cells but not conventional CD4+ T cells was significantly impaired in Nf-κb1-/- mice compared with that in WT mice. RNA-sequencing analyses revealed that the expression of E2 factor target genes was decreased in Vγ4+Vδ4+γδT cells by the absence of NF-κB1. Consistently, the cell cycle progression of Vγ4+Vδ4+γδT cells was reduced in Nf-κb1-/- mice compared with that in WT mice. These results suggest that Nf-κb1 plays a crucial role in the pathogenesis of imiquimod-induced psoriasis-like skin inflammation by promoting the proliferation of Vγ4+Vδ4+γδT17 cells.
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Dermatitis , Psoriasis , Animales , Dermatitis/patología , Modelos Animales de Enfermedad , Imiquimod , Inflamación/patología , Interleucina-17/metabolismo , Ratones , Ratones Endogámicos BALB C , Psoriasis/inducido químicamente , Psoriasis/genética , Psoriasis/metabolismo , Piel/patologíaRESUMEN
Post-transcriptional regulation is involved in the regulation of many inflammatory genes. Zinc finger protein 36 (ZFP36) family proteins are RNA-binding proteins involved in messenger RNA (mRNA) metabolism pathways. The ZFP36 family is composed of ZFP36 (also known as tristetraprolin, TTP), ZFP36L1, ZFP36L2, and ZFP36L3 (only in rodents). The ZFP36 family proteins contain two tandemly repeated CCCH-type zinc-finger motifs, bind to adenine uridine-rich elements in the 3'-untranslated regions (3' UTR) of specific mRNA, and lead to target mRNA decay. Although the ZFP36 family members are structurally similar, they are known to play distinct functions and regulate different target mRNAs, probably due to their cell-type-specific expression patterns. For instance, ZFP36 has been well-known to function as an anti-inflammatory modulator in murine models of systemic inflammatory diseases by down-regulating the production of various pro-inflammatory cytokines, including TNF-α. Meanwhile, ZFP36L1 is required for the maintenance of the marginal-zone B cell compartment. Recently, we found that ZFP36L2 reduces the expression of Ikzf2 (encoding HELIOS) and suppresses regulatory T cell function. This review summarizes the current understanding of the post-transcriptional regulation of immunological responses and inflammatory diseases by RNA-binding ZFP36 family proteins.
Asunto(s)
Inmunidad/genética , Inflamación/genética , Familia de Multigenes , Interferencia de ARN , Tristetraprolina/fisiología , Regiones no Traducidas 3' , Animales , Enfermedades Autoinmunes/genética , Citocinas/genética , Terapia Genética , Vectores Genéticos/uso terapéutico , Estudio de Asociación del Genoma Completo , Humanos , Hipersensibilidad/genética , Inflamación/terapia , Ratones , Polimorfismo de Nucleótido Simple , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/fisiología , Relación Estructura-Actividad , Tristetraprolina/genética , Dedos de ZincRESUMEN
T-bet and signal transducer and activator of transcription (STAT) 6 are critical factors for helper T-cell differentiation in humans and mice. Additionally, polymorphisms in TBX21 (T-bet) and STAT6 are associated with the susceptibility of allergic diseases. However, precise mechanisms of the reciprocal regulation between T-bet and STAT6 in allergy remain unclear. To determine the reciprocal regulation in vivo, we investigated the phenotype of T-bet/STAT6 double-deficient (T-bet-/- STAT6-/-) mice. Unexpectedly, T-bet-/- STAT6-/- mice but not T-bet-/- mice or STAT6-/- mice spontaneously developed severe dermatitis. Not only eosinophils and mast cells but also CD4+ T cells infiltrated into the skin of T-bet-/- STAT6-/- mice. Adoptive transfer of CD4+ T cells of T-bet-/- STAT6-/- mice into severe combined immunodeficient mice induced the accumulation of eosinophils and mast cells in the skin, whereas depletion of CD4+ T cells ameliorated the dermatitis in T-bet-/- STAT6-/- mice. Comprehensive transcriptome analyses revealed that IL-9 expression was enhanced in T-bet-/- STAT6-/- CD4+ T cells. Indeed, IL-9 neutralization ameliorated the dermatitis in T-bet-/- STAT6-/- mice. T-bet-/- STAT6-/- CD4+ T cells expressed functional thymic stromal lymphopoietin receptors and produced large amounts of IL-9 on thymic stromal lymphopoietin stimulation. These results indicate that T-bet and STAT6 coordinately suppress atopic dermatitis-like skin inflammation, possibly by inhibiting thymic stromal lymphopoietin-dependent IL-9 production in CD4+ T cells.
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Dermatitis Atópica/prevención & control , Interleucina-9/fisiología , Factor de Transcripción STAT6/fisiología , Proteínas de Dominio T Box/fisiología , Animales , Linfocitos T CD4-Positivos/inmunología , Citocinas/fisiología , Ratones , Ratones Endogámicos BALB C , Linfopoyetina del Estroma TímicoRESUMEN
The zinc finger protein 36-like 2, ZFP36L2, is a member of a small family of RNA-binding proteins composed by ZFP36 (also known as tristetraprolin, TTP), ZFP36L1 and ZFP36L2 in humans, with corresponding murine orthologs. These proteins bind to adenine uridine-rich element (ARE) in the 3'untranslated region of target messenger RNA and stimulate target degradation. ZFP36 functions as an anti-inflammatory modulator in murine models of inflammatory diseases by down-regulating the production of inflammatory cytokines such as tumor necrosis factor-α. However, how ZFP36L1 and ZFP36L2 alter the function of CD4+ T cells is not completely understood. We addressed this issue by searching for the target genes of ZFP36L2 by comprehensive transcriptome analysis. We observed that ZFP36L2 is highly expressed in naïve CD4+ T cells; however, when CD4+ T cells are stimulated through their T cell receptors, ZFP36L2 expression is rapidly reduced in both humans and mice. Among CD4+ T cell populations, the expression levels of ZFP36L2 in regulatory T cells (Tregs) were significantly lower than those in naïve or effector CD4+ T cells. RNA-sequence analysis revealed that the forced expression of ZFP36L2 decreased Ikzf2 (encoding Helios) expression in Foxp3+ Tregs and inhibited the ability of induced Tregs (iTregs). ZFP36L2 directly bound to and destabilized the 3'untranslated region of Ikzf2 mRNA, which contains AU-rich elements. These results indicate that ZFP36L2 reduces the expression of Ikzf2 and suppresses iTreg function, raising the interesting possibility that the inhibition of ZFP36L2 in iTregs could be a therapeutic strategy for autoimmune diseases.
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Proteínas de Unión al ADN/biosíntesis , Regulación de la Expresión Génica/inmunología , Factor de Transcripción Ikaros/biosíntesis , Linfocitos T Reguladores/inmunología , Factores de Transcripción/biosíntesis , Factores de Transcripción/inmunología , Tristetraprolina/inmunología , Animales , Proteínas de Unión al ADN/inmunología , Regulación hacia Abajo , Humanos , Factor de Transcripción Ikaros/inmunología , Ratones , Factores de Transcripción/metabolismo , Tristetraprolina/metabolismoRESUMEN
OBJECTIVE: Musculoskeletal ultrasound (US) is more sensitive than physical examination in detecting synovitis and helps physicians to understand its pathophysiology. In this study, we aimed to determine if the experience in musculoskeletal US scanning is independently associated with improved physical examination skills to detect synovitis. METHOD: Seventy patients with rheumatoid arthritis and twenty-three physicians were enrolled. Patients were first assessed by multiple physicians with a range of clinical/sonographic experience for the swelling of the wrist, metacarpophalangeal and proximal interphalangeal (PIP) joints and next underwent US assessment performed by another physician experienced in musculoskeletal US. We then calculated the positive/negative predictive values (PPV/NPV) of joint swelling to identify US-detected synovial hypertrophy. Finally, the factors independently associated with the accuracy of clinical assessment were identified by using multivariate analyses. RESULTS: One thousand five hundred forty joints were assessed 6116 times in total for swelling. Overall, PPV and NPV of joint swelling were 51.7% and 88.3%, respectively. Multivariate analyses identified wrist joint, tenderness, male and greater patients' age as the factors significantly associated with higher PPV. In addition, there was a trend that longer experience in rheumatology clinical practice was associated with higher PPV (p = 0.058). On the other hand, longer experience in musculoskeletal US, PIP joint and positive rheumatoid factor were identified as the significant factors for higher NPV, while wrist joint, tenderness, presence of osteophyte and obesity as those for lower NPV. CONCLUSION: Our data suggest that the experience in musculoskeletal US improves physical examination skills particularly to avoid overestimation.Key Points⢠Physicians with longer US experience are less likely to overestimate synovitis by physical examination.⢠Musculoskeletal US is a useful tool for rheumatologists to improve their physical examination skill.⢠Presence of osteophytes, joint tenderness and obesity influence the accuracy of physical examination of joints.
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Artritis Reumatoide/diagnóstico , Edema/diagnóstico , Sinovitis/diagnóstico , Ultrasonografía , Articulación de la Muñeca/patología , Anciano , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico por imagen , Competencia Clínica , Edema/diagnóstico por imagen , Edema/etiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Examen Físico , Valor Predictivo de las Pruebas , Reumatólogos/normas , Sinovitis/diagnóstico por imagen , Sinovitis/etiología , Articulación de la Muñeca/diagnóstico por imagenAsunto(s)
Hipersensibilidad a los Alimentos/inmunología , Interleucinas/inmunología , Intestinos/inmunología , Mastocitos/inmunología , Animales , Hipersensibilidad a los Alimentos/genética , Hipersensibilidad a los Alimentos/patología , Interleucinas/genética , Intestinos/patología , Mastocitos/patología , Ratones , Ratones NoqueadosRESUMEN
Clinical manifestations of systemic lupus erythematosus (SLE) in female patients with polysomy X have been less characterized as compared to those in male patients. Here, we describe a 28-year-old woman with trisomy X (47,XXX) who developed SLE. She had polyarthritis, hemolytic anemia, and was positive for anti-nuclear and anti-dsDNA antibodies. We discuss the common SLE manifestations with female polysomy X and the possible link between the development of SLE and the presence of extra X-chromosomes.
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Lupus Eritematoso Sistémico/patología , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/complicaciones , Adulto , Cromosomas Humanos X/genética , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Aberraciones Cromosómicas Sexuales , TrisomíaRESUMEN
Interleukin-33 (IL-33) plays multiple roles in tissue homeostasis, prevention of parasitic infection, and induction of allergic inflammation. Especially, IL-33-ST2 (IL-1RL1) axis has been regarded as the villain in allergic diseases such as asthma and atopic dermatitis and in autoimmune diseases such as rheumatoid arthritis. Indeed, a number of studies have indicated that IL-33 produced by endothelial cells and epithelial cells plays a critical role in the activation and expansion of group 2 innate lymphoid cells (ILC2s) which cause allergic inflammation by producing large amounts of IL-5 and IL-13. However, mechanisms that antagonize IL-33-ST2-mediated allergic responses remain largely unknown. Recently, several groups including our group have demonstrated cellular and molecular mechanisms that could suppress excessive activation of ILC2s by the IL-33-ST2 axis. In this review, we summarize recent progress in the regulatory mechanisms of IL-33-ST2-mediated allergic responses. Selective targeting of the IL-33-ST2 axis would be a promising strategy in the treatment of allergic diseases.
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Hipersensibilidad/inmunología , Inflamación/inmunología , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Linfocitos/inmunología , Animales , Humanos , Tolerancia Inmunológica , Inmunomodulación , Activación de Linfocitos , Transducción de Señal , Células Th2/inmunologíaRESUMEN
BACKGROUND: Innate lymphoid cells (ILCs) are emerging subsets of immune cells that produce large amounts of cytokines upon cytokine and/or alarmin stimulation. Recent studies have shown that T-bet plays pivotal roles in the development of ILC3s and type 1 ILCs; however, the roles of T-bet in lung type 2 innate lymphoid cells (ILC2s) remain unknown. OBJECTIVE: We sought to determine the role of T-bet in ILC2-mediated airway inflammation. METHODS: The expression of T-bet in lung ILCs (defined as Thy1.2+ Lin- cells) was examined. The roles of T-bet in the development of lung ILC2s and airway inflammation induced by IL-33 administration were examined by using T-bet-deficient (T-bet-/-) mice. Gene expression profiles of T-bet-/- lung ILCs were analyzed by RNA sequencing. RESULTS: T-bet was expressed in lung ILC2s (defined as Thy1.2+ Lin- cells expressing ST2 or CD25) and IFN-γ enhanced its expression. Although the development of lung ILC2s at steady-state conditions was normal in T-bet-/- mice, IL-33-induced accumulation of lung ILC2s and eosinophilic airway inflammation were exacerbated in T-bet-/- mice. The exacerbated accumulation of ILC2s and eosinophilic airway inflammation by the absence of T-bet were evident even in a RAG2-/- background, suggesting that T-bet expressed in non-T/non-B population is involved in the suppression of IL-33-induced eosinophilic airway inflammation. Transcriptome analysis revealed that IL-9 expression in IL-33-stimulated lung ILCs was upregulated in T-bet-/- mice compared with that in wild-type mice. Importantly, neutralization of IL-9 markedly attenuated IL-33-induced accumulation of lung ILC2s and eosinophilic inflammation in T-bet-/- mice. CONCLUSIONS: T-bet suppresses IL-9 production from lung ILC2s and thereby inhibits IL-33-induced eosinophilic airway inflammation.
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Inmunidad Innata/inmunología , Interleucina-9/biosíntesis , Subgrupos Linfocitarios/inmunología , Neumonía/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Interleucina-33/biosíntesis , Interleucina-33/inmunología , Interleucina-9/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neumonía/metabolismo , Reacción en Cadena de la Polimerasa , Eosinofilia Pulmonar/inmunología , Eosinofilia Pulmonar/metabolismo , Proteínas de Dominio T Box/metabolismo , Antígenos Thy-1RESUMEN
INTRODUCTION: This study aimed to investigate the efficacy of abatacept for arthritis in patients with rhupus, an overlap syndrome between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: Patients who fulfilled both the 2010 ACR/EULAR criteria for RA classification and the 1997 ACR revised criteria for classification of SLE and received abatacept treatment for arthritis were retrospectively studied. RESULTS: Six rhupus patients who fulfilled the inclusion criteria above were identified. All patients had active arthritis despite receiving antirheumatic drugs including methotrexate when abatacept was initiated. Clinical Disease Activity Index (CDAI) significantly decreased between baseline and 12 weeks (P = 0.028) and remained low through 24 weeks. All patients achieved either a good or moderate response according to the EULAR response criteria at 24 weeks. Health Assessment Questionnaire-Disability Index (HAQ-DI) also significantly decreased between baseline and 24 weeks (P = 0.043). In addition, the levels of immunoglobulin G and anti-DNA antibody significantly decreased between baseline and 24 weeks (P = 0.028 and P = 0.043, resp.). CONCLUSIONS: Treatment with abatacept is likely to be efficacious in patients with rhupus whose arthritis is refractory to methotrexate. In addition, abatacept may have a moderate effect on abnormal antibody production in rhupus patients.