RESUMEN
OBJECTIVES: Osteoclasts (OCs) are myeloid-derived multinucleated cells uniquely able to degrade bone. However, the exact nature of their myeloid precursors is not yet defined. METHODS: CD11c-diphtheria toxin receptor (CD11cDTR) transgenic mice were treated with diphtheria toxin (DT) or phosphate buffered saline (PBS) during serum transfer arthritis (STA) and human tumour necrosis factor transgenic (hTNFtg) arthritis and scored clinically and histologically. We measured cytokines in synovitis by quantitative polymerase chain reaction (qPCR). We performed ovariectomy in CD11cDTR mice treated with PBS or DT. We analysed CD11cDTR, CD11c-Cre/CX3CR1-STOP-DTR and Zbtb46-DTR-treated mice with DT using histomorphometry and OC of CD11c and Zbtb46 fate reporter mice by fluorescent imaging. We sorted murine and human OC precursors and stimulated them with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) to generate OCs. RESULTS: Targeting CD11c+ cells in vivo in models of inflammatory arthritis (STA and hTNFtg) ameliorates arthritis by reducing inflammatory bone destruction and OC generation. Targeting CD11c-expressing cells in unchallenged mice removes all OCs in their long bones. OCs do not seem to be derived from CD11c+ cells expressing CX3CR1+, but from Zbtb46+conventional dendritic cells (cDCs) as all OCs in Zbtb46-Tomato fate reporter mice are Tomato+. In line, administration of DT in Zbtb46-DTR mice depletes all OCs in long bones. Finally, human CD1c-expressing cDCs readily differentiated into bone resorbing OCs. CONCLUSION: Taken together, we identify DCs as important OC precursors in bone homeostasis and inflammation, which might open new avenues for therapeutic interventions in OC-mediated diseases.
Asunto(s)
Artritis , Osteoclastos , Femenino , Ratones , Humanos , Animales , Citocinas/metabolismo , Diferenciación Celular , Artritis/metabolismo , Células Dendríticas/metabolismo , Ligando RANK/metabolismoRESUMEN
Chronic exposure to high-fat diets (HFD) worsens intestinal disease pathology, but acute effects of HFD in tissue damage remain unclear. Here, we used short-term HFD feeding in a model of intestinal injury and found sustained damage with increased cecal dead neutrophil accumulation, along with dietary lipid accumulation. Neutrophil depletion rescued enhanced pathology. Macrophages from HFD-treated mice showed reduced capacity to engulf dead neutrophils. Macrophage clearance of dead neutrophils activates critical barrier repair and antiinflammatory pathways, including IL-10, which was lost after acute HFD feeding and intestinal injury. IL-10 overexpression restored intestinal repair after HFD feeding and intestinal injury. Macrophage exposure to lipids from the HFD prevented tethering and uptake of apoptotic cells and Il10 induction. Milk fat globule-EGF factor 8 (MFGE8) is a bridging molecule that facilitates macrophage uptake of dead cells. MFGE8 also facilitates lipid uptake, and we demonstrate that dietary lipids interfere with MFGE8-mediated macrophage apoptotic neutrophil uptake and subsequent Il10 production. Our findings demonstrate that HFD promotes intestinal pathology by interfering with macrophage clearance of dead neutrophils, leading to unresolved tissue damage.
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Dieta Alta en Grasa , Interleucina-10 , Ratones , Animales , Intestinos , Macrófagos/fisiología , LípidosRESUMEN
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4-mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.
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Colitis , Interleucina-6 , Ratones , Animales , Calidad de Vida , Colitis/patología , Inmunoterapia , InflamaciónRESUMEN
Inflammatory bowel disease (IBD) is a chronic life-long inflammatory disease affecting almost 2 million Americans. Although new biologic therapies have been developed, the standard medical treatment fails to selectively control the dysregulated immune pathways involved in chronic colonic inflammation. Further, IBD patients with uncontrolled colonic inflammation are at a higher risk for developing colorectal cancer (CRC). Intestinal microbes can impact many immune functions, and here we asked if they could be used to improve intestinal inflammation. By utilizing an intestinal adherent E. coli that we find increases IL-10 producing macrophages, we were able to limit intestinal inflammation and restrict tumor formation. Macrophage IL-10 along with IL-10 signaling to the intestinal epithelium were required for protection in both inflammation and tumor development. Our work highlights that administration of immune modulating microbes can improve intestinal outcomes by altering tissue inflammation.
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Neoplasias Asociadas a Colitis , Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Microbiota , Animales , Modelos Animales de Enfermedad , Escherichia coli , Humanos , Inflamación , Enfermedades Inflamatorias del Intestino/terapia , Interleucina-10 , MacrófagosRESUMEN
The gut microbiota is essential for maintenance and repair of the intestinal epithelial barrier. As shifts in both intestinal epithelial barrier function and microbiota composition are found in inflammatory bowel disease patients, it is critical to understand the role of distinct bacteria in regulating barrier repair. We identified a mouse commensal E. coli isolate, GDAR2-2, that protects mice from Citrobacter rodentium infection and dextran sulfate sodium-induced colitis. Colonization with GDAR2-2 in mice resulted in expansion of CX3CR1+ mononuclear phagocytes, including CX3CR1+ macrophages/dendritic cells and monocytes, along with IL-22-secreting type 3 innate lymphoid cells and improved epithelial barrier function. In vitro co-culture of macrophages with GDAR2-2 resulted in IL-1ß production. In vivo, protection after GDAR2-2 colonization was lost after depletion of CX3CR1+ MNPs, or blockade of IL-1ß or IL-22. We further identified human commensal E. coli isolates that similarly protect mice from C. rodentium infection through CX3CR1+ MNP and IL-1ß production. Together, these findings demonstrate an unexpected role for commensal bacteria in promoting IL-1ß secretion to support intestinal barrier repair.
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Colitis/metabolismo , Colitis/fisiopatología , Microbioma Gastrointestinal , Interleucina-18/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Simbiosis , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Fenómenos Fisiológicos Bacterianos , Colitis/genética , Colitis/microbiología , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BLRESUMEN
Microbiota-specific T cell responses have been identified for select microbes, but individual T cell receptor repertoire differences make characterizing responses across populations difficult. In this issue of Immunity, Muschaweck et al. establish a system allowing for reproducible responses between individual mice, a powerful tool for characterizing microbiota directed immunity.
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Microbiota , Linfocitos T , Animales , Ratones , Receptores de Antígenos de Linfocitos TRESUMEN
Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection1. Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen while limiting inflammatory anti-commensal responses1,2. Antigen-specific recognition of intestinal microorganisms by T cells has previously been described3,4. Although the local environment shapes the differentiation of effector cells3-5 it is unclear how microbiota-specific T cells are educated in the thymus. Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens.
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Células Dendríticas/inmunología , Microbioma Gastrointestinal/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Timo/citología , Timo/inmunología , Envejecimiento/inmunología , Animales , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/metabolismo , Receptor 1 de Quimiocinas CX3C/metabolismo , ADN Bacteriano/análisis , Células Dendríticas/metabolismo , Escherichia coli/inmunología , Femenino , Masculino , Ratones , Especificidad de Órganos , Salmonella/inmunología , Simbiosis/inmunología , Timo/metabolismoRESUMEN
During both health and disease, a coordinated response between the epithelium, immune system, and enteric nervous system is required for proper intestinal function. While each system responds to a number of common stimuli, their coordinated responses support digestion as well as responses and recovery following injury or pathogenic infections. In this review, we discuss how individual responses to common signals work together to support these critical functions.
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Sistema Nervioso Entérico/fisiología , Epitelio/fisiología , Microbioma Gastrointestinal , Interacciones Microbiota-Huesped , Inmunidad , Intestinos/inmunología , Intestinos/microbiología , Humanos , Mucosa Intestinal/fisiologíaRESUMEN
Adherent-invasive E. coli (AIEC) are enriched in the intestinal microbiota of patients with Crohn's disease (CD) and promote intestinal inflammation. Yet, how AIEC metabolism of nutrients impacts intestinal homeostasis is poorly defined. Here, we show that AIEC encoding the large subunit of propanediol dehydratase (PduC), which facilitates the utilization of fucose fermentation product 1,2-propanediol, are increased in the microbiome of CD patients and drive AIEC-induced intestinal T cell inflammation. In murine models, CX3CR1+ mononuclear phagocytes (MNP) are required for PduC-dependent induction of T helper 17 (Th17) cells and interleukin-1ß (IL-1ß) production that leads to AIEC-induced inflammatory colitis. Activation of this inflammatory cascade requires the catalytic activity of PduC to generate propionate, which synergizes with lipopolysaccharide (LPS) to induce IL-1ß by MNPs. Disrupting fucose availability limits AIEC-induced propionate production and intestinal inflammation. These findings identify MNPs as metabolic sensors linking AIEC metabolism with intestinal inflammation and identify microbial metabolism as a potential therapeutic target in Crohn's disease treatment.
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Enfermedad de Crohn/metabolismo , Infecciones por Escherichia coli/metabolismo , Escherichia coli/metabolismo , Inflamación/metabolismo , Intestinos/inmunología , Fagocitos/metabolismo , Glicoles de Propileno/metabolismo , Animales , Adhesión Bacteriana , Enfermedad de Crohn/microbiología , Infecciones por Escherichia coli/microbiología , Femenino , Interacciones Huésped-Patógeno , Humanos , Inmunidad , Interleucina-1beta , Mucosa Intestinal/metabolismo , Intestinos/microbiología , Masculino , Ratones , Fagocitos/inmunología , Células Th17RESUMEN
Autoimmune diseases and chronic inflammatory disorders are characterized by dysregulated immune responses resulting in excessive and uncontrolled tissue inflammation. Multiple factors including genetic variation, environmental stimuli, and infection are all thought to contribute to continued inflammation and pathology. Current evidence supports the microbiota as one such factor with emerging data linking commensal organisms to the onset and progression of disease. In this review, we will discuss links between the microbiota and specific diseases as well as highlight common pathways that link intestinal microbes with multiple autoimmune and inflammatory diseases.
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Enfermedades Autoinmunes/etiología , Autoinmunidad , Susceptibilidad a Enfermedades , Microbioma Gastrointestinal , Inflamación/etiología , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/metabolismo , Susceptibilidad a Enfermedades/inmunología , Disbiosis/inmunología , Microbioma Gastrointestinal/inmunología , Humanos , Inflamación/diagnóstico , Inflamación/metabolismo , Especificidad de Órganos/inmunologíaRESUMEN
Alteration of innate immune cells in the lungs can promote loss of peripheral tolerance that leads to autoimmune responses in cigarette smokers. Development of autoimmunity in smokers with emphysema is also strongly linked to the expansion of autoreactive T helper (Th) cells expressing interferon gamma (Th1), and interleukin 17A (Th17). However, the mechanisms responsible for enhanced self-recognition and reduced immune tolerance in smoker with emphysema remain less clear. Here we show that C1q, a component of the complement protein 1 complex (C1), is downregulated in lung CD1a+ antigen presenting cells (APCs) isolated from emphysematous human, and mouse lung APCs after chronic cigarette smoke exposure. C1q potentiated the function of APCs to differentiate CD4+ T cells to Tregs, while it inhibited Th17 cell development and proliferation. Mice deficient in C1q that were exposed to chronic smoke exhibited exaggerated lung inflammation marked by increased Th17 cells, while reconstitution of C1q in the lungs enhanced Tregs abundance, dampened smoke-induced lung inflammation, and reversed established emphysema. Our findings demonstrate that cigarette smoke-mediated loss of C1q could play a key role in reduced peripheral tolerance, which could be explored to treat emphysema.
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Células Presentadoras de Antígenos/metabolismo , Fumar Cigarrillos/efectos adversos , Complemento C1q/metabolismo , Enfisema/inmunología , Células Th17/inmunología , Adulto , Anciano , Animales , Células Presentadoras de Antígenos/inmunología , Autoinmunidad , Estudios de Casos y Controles , Diferenciación Celular/inmunología , Proliferación Celular , Células Cultivadas , Fumar Cigarrillos/inmunología , Técnicas de Cocultivo , Complemento C1q/genética , Complemento C1q/inmunología , Modelos Animales de Enfermedad , Regulación hacia Abajo/inmunología , Enfisema/patología , Femenino , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Tolerancia Inmunológica , Pulmón/citología , Pulmón/inmunología , Pulmón/patología , Activación de Linfocitos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Cultivo Primario de Células , Humo/efectos adversos , Linfocitos T Reguladores/inmunología , Análisis de Matrices Tisulares , Productos de Tabaco/efectos adversosRESUMEN
In a recent study, Harrison et al. (Science 2019;363;eaat6280) report that RORγt-expressing skin commensal-specific T cells rapidly respond to tissue wounding by producing type 2 T helper cell (Th2) cytokines in mice. The cells constitutively coexpress GATA-3 and type 2 cytokine mRNAs that are translated after injury. These T cells act as sentinels, linking T cell receptor (TCR) recognition of commensals, tissue damage, and wound repair.
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Microbiota/inmunología , Células Th2/inmunología , Cicatrización de Heridas , Animales , Citocinas/metabolismo , Humanos , Inmunidad Celular , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
Epidemiological evidence finds cigarette smoking is a common risk factor for a number of diseases, not only in the lung but also in other tissues, such as the gastrointestinal tract. While it is well-documented that smoking directly drives lung inflammatory disease, how it promotes disease in peripheral tissues is incompletely understood. In this study, we utilized a mouse model of short-term smoke exposure and found increased Th17 cells and neutrophilia in the lung as well as in the circulation. Following intestinal inflammatory challenge, smoke exposed mice showed increased pathology which corresponds to enhanced intestinal Th17 cells, ILC3 and neutrophils within intestinal tissue. Using cellular depletion and genetic deficiencies, we define a cellular loop by which IL-17A and downstream neutrophils drive cigarette smoke-enhanced intestinal inflammation. Collectively, cigarette smoke induced local lung Th17 responses lead to increased systemic susceptibility to inflammatory insult through enhanced circulating neutrophils. These data demonstrate a cellular pathway by which inflammatory challenge in the lung can sensitize the intestine to enhanced pathological innate and adaptive immune responses.
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Intestinos/efectos de los fármacos , Pulmón/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Humo/efectos adversos , Células Th17/efectos de los fármacos , Productos de Tabaco , Animales , Colitis/inducido químicamente , Colitis/inmunología , Colitis/patología , Citocinas/genética , Citocinas/inmunología , Femenino , Intestinos/inmunología , Intestinos/patología , Pulmón/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Células Th17/inmunologíaRESUMEN
Intestinal damage driven by unrestricted immune responses against the intestinal microbiota can lead to the development of inflammatory diseases including inflammatory bowel disease. How such breakdown in tolerance occurs alongside the mechanisms to reinforce homeostasis with the microbiota are a focus of many studies. Our recent work demonstrates coordinated interactions between intact microbiota and CX3CR1 expressing intestinal antigen presenting cells (APCs) that limits T helper 1 cell responses and promotes differentiation of regulatory T cells (Treg) against intestinal antigens including pathogens, soluble proteins and the microbiota itself. We find a microbial attachment to intestinal epithelial cells is necessary to support these anti-inflammatory immune functions. In this addendum, we discuss how our findings enhance understanding of microbiota-directed homeostatic functions of the intestinal immune system and implications of modulating this interaction in ameliorating inflammatory disease.
RESUMEN
Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Genetic studies have linked TNFSF15 polymorphisms and its protein TNF-like ligand 1A (TL1A) with IBD, but the functional role of TL1A is not known. Here, we found that adherent IBD-associated microbiota induced TL1A release from CX3CR1+ mononuclear phagocytes (MNPs). Using cell-specific genetic deletion models, we identified an essential role for CX3CR1+MNP-derived TL1A in driving group 3 innate lymphoid cell (ILC3) production of interleukin-22 and mucosal healing during acute colitis. In contrast to this protective role in acute colitis, TL1A-dependent expression of co-stimulatory molecule OX40L in MHCII+ ILC3s during colitis led to co-stimulation of antigen-specific T cells that was required for chronic T cell colitis. These results identify a role for ILC3s in activating intestinal T cells and reveal a central role for TL1A in promoting ILC3 barrier immunity during colitis.
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Colitis/inmunología , Inmunidad Innata/inmunología , Linfocitos/inmunología , Microbiota/inmunología , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunología , Adulto , Anciano , Animales , Colitis/genética , Colitis/metabolismo , Femenino , Humanos , Inmunidad Innata/genética , Interleucinas/genética , Interleucinas/inmunología , Interleucinas/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microbiota/fisiología , Persona de Mediana Edad , Fagocitos/citología , Fagocitos/inmunología , Fagocitos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Adulto Joven , Interleucina-22RESUMEN
Intestinal homeostasis requires microbial recognition that results in appropriate responses to commensals and pathogens. In this issue of Immunity, Price et al. (2018) map the in vivo expression of five toll-like receptors (TLR) in intestinal epithelia, revealing distinct spatio-temporal expression patterns that shape responses to TLR ligands.
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Mucosa Intestinal , Receptores Toll-Like , Inmunidad , LigandosRESUMEN
The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX3CR1 reduced expansion of intestinal microbe-specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CX3CR1+ APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss, indicating that although microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis.
Asunto(s)
Receptor 1 de Quimiocinas CX3C/metabolismo , Microbioma Gastrointestinal/inmunología , Mucosa Intestinal/inmunología , Sistema Mononuclear Fagocítico/inmunología , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Animales , Presentación de Antígeno , Adhesión Bacteriana/inmunología , Modelos Animales de Enfermedad , Femenino , Homeostasis , Tolerancia Inmunológica , Inmunidad Mucosa , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-10/inmunología , Interleucina-10/metabolismo , Mucosa Intestinal/microbiología , Masculino , Ratones , Células RAW 264.7RESUMEN
Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non-small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which Pten and Smad4 (Pts4d/d ) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. Pts4d/d mice globally lacking in IL17a (Pts4d/dIl17a-/- ) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103+ dendritic cells, and adoptive transfer of IL17a-sufficient CD4+ T cells reversed early tumor development and metastasis in Pts4d/dIl17a-/- mice. Together, these findings support a key role for Th17 cells in TILs associated with the Pts4d/d model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. Cancer Immunol Res; 6(6); 645-57. ©2018 AACR.
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Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Interleucina-17/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/genética , Animales , Biomarcadores , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/genética , Ciclo Celular/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Genómica/métodos , Humanos , Inmunohistoquímica , Inmunofenotipificación , Interleucina-17/genética , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Noqueados , Metástasis de la Neoplasia , Estadificación de Neoplasias , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/patologíaRESUMEN
Peripheral spondyloarthritis (SpA) is a common extraintestinal manifestation in patients with active inflammatory bowel disease (IBD) characterized by inflammatory enthesitis, dactylitis, or synovitis of nonaxial joints. However, a mechanistic understanding of the link between intestinal inflammation and SpA has yet to emerge. We evaluated and functionally characterized the fecal microbiome of IBD patients with or without peripheral SpA. Coupling the sorting of immunoglobulin A (IgA)-coated microbiota with 16S ribosomal RNA-based analysis (IgA-seq) revealed a selective enrichment in IgA-coated Escherichia coli in patients with Crohn's disease-associated SpA (CD-SpA) compared to CD alone. E. coli isolates from CD-SpA-derived IgA-coated bacteria were similar in genotype and phenotype to an adherent-invasive E. coli (AIEC) pathotype. In comparison to non-AIEC E. coli, colonization of germ-free mice with CD-SpA E. coli isolates induced T helper 17 cell (TH17) mucosal immunity, which required the virulence-associated metabolic enzyme propanediol dehydratase (pduC). Modeling the increase in mucosal and systemic TH17 immunity we observed in CD-SpA patients, colonization of interleukin-10-deficient or K/BxN mice with CD-SpA-derived E. coli lead to more severe colitis or inflammatory arthritis, respectively. Collectively, these data reveal the power of IgA-seq to identify immunoreactive resident pathosymbionts that link mucosal and systemic TH17-dependent inflammation and offer microbial and immunophenotype stratification of CD-SpA that may guide medical and biologic therapy.
Asunto(s)
Enfermedad de Crohn/inmunología , Enfermedad de Crohn/microbiología , Escherichia coli/metabolismo , Inmunoglobulina A/metabolismo , Inflamación/patología , Espondiloartritis/inmunología , Espondiloartritis/microbiología , Células Th17/inmunología , Animales , Biomarcadores/metabolismo , Colitis/inducido químicamente , Colitis/inmunología , Colitis/microbiología , Enfermedad de Crohn/complicaciones , Sulfato de Dextran , Epitelio/inmunología , Escherichia coli/aislamiento & purificación , Humanos , Inmunidad Mucosa , Inmunofenotipificación , Inflamación/complicaciones , Interleucina-10/metabolismo , Interleucina-23/metabolismo , Intestinos/microbiología , Articulaciones/patología , Ratones Endogámicos C57BL , Espondiloartritis/complicacionesRESUMEN
While acute infections cause short-term tissue damage, their long-term impact remains unknown. In a recent publication in Cell, Morais da Fonseca et al. (2015) demonstrate disruption of mesenteric lymph nodes and associated lymphatics after Yersinia pseudotuberculosis infection and clearance. This leads to chronic inflammation and an inability to initiate subsequent intestinal immune responses.