RESUMEN
The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the immune system has a second major function: the maintenance of organismal homeostasis. Foxp3(+)CD4(+) regulatory T cells (Tregs) are important contributors to both of these critical activities, defense being the primary purview of Tregs circulating through lymphoid organs, and homeostasis ensured mainly by their counterparts residing in parenchymal tissues. This review focuses on so-called tissue Tregs. We first survey existing information on the phenotype, function, sustaining factors, and human equivalents of the three best-characterized tissue-Treg populations-those operating in visceral adipose tissue, skeletal muscle, and the colonic lamina propria. We then attempt to distill general principles from this body of work-as concerns the provenance, local adaptation, molecular sustenance, and targets of action of tissue Tregs, in particular.
Asunto(s)
Tejido Adiposo/inmunología , Colon/inmunología , Membrana Mucosa/inmunología , Músculo Esquelético/inmunología , Linfocitos T Reguladores/inmunología , Animales , Factores de Transcripción Forkhead/metabolismo , Homeostasis , Humanos , Especificidad de ÓrganosRESUMEN
The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology and gastrointestinal (GI) disease. Here, we report genetically defined subsets of colon-innervating DRG neurons with diverse morphologic and physiologic properties. Four colon-innervating DRG neuron populations are mechanosensitive and exhibit distinct force thresholds to colon distension. The highest threshold population, selectively labeled using Bmpr1b genetic tools, is necessary and sufficient for behavioral responses to high colon distension, which is partly mediated by the mechanosensory ion channel Piezo2. This Aδ-HTMR population mediates behavioral over-reactivity to colon distension caused by inflammation in a model of inflammatory bowel disease. Thus, like cutaneous DRG mechanoreceptor populations, colon-innervating mechanoreceptors exhibit distinct anatomical and physiological properties and tile force threshold space, and genetically defined colon-innervating HTMRs mediate pathophysiological responses to colon distension, revealing a target population for therapeutic intervention.
Asunto(s)
Ganglios Espinales , Mecanorreceptores , Mecanorreceptores/fisiología , Colon , Neuronas , Piel/inervaciónRESUMEN
The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.
Asunto(s)
Diferenciación Celular , Colitis , Células Dendríticas , Células T Auxiliares Foliculares , Animales , Células Dendríticas/inmunología , Colitis/inmunología , Colitis/patología , Células T Auxiliares Foliculares/inmunología , Ratones , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Células TH1/inmunología , Colon/inmunología , Colon/patología , Ratones Noqueados , Centro Germinal/inmunología , Ratones TransgénicosRESUMEN
To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from patients with UC and controls. Here we identified colonic CD4+ and CD8+ T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in several mouse models of autoimmune disease. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to proinflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model in mice, we demonstrated that CD4+ T cells deficient in either BCL-6 or TCF1, transcription factors that promote T cell stemness, had decreased colon T cells and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes.
Asunto(s)
Colitis Ulcerosa , Factor Nuclear 1-alfa del Hepatocito , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Humanos , Animales , Ratones , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Células Madre/inmunología , Células Madre/metabolismo , Femenino , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Ratones Noqueados , Colon/inmunología , Colon/patología , Masculino , Ratones Endogámicos C57BL , Traslado Adoptivo , Modelos Animales de Enfermedad , Adulto , Persona de Mediana EdadRESUMEN
Spatial barcoding technologies have the potential to reveal histological details of transcriptomic profiles; however, they are currently limited by their low resolution. Here, we report Seq-Scope, a spatial barcoding technology with a resolution comparable to an optical microscope. Seq-Scope is based on a solid-phase amplification of randomly barcoded single-molecule oligonucleotides using an Illumina sequencing platform. The resulting clusters annotated with spatial coordinates are processed to expose RNA-capture moiety. These RNA-capturing barcoded clusters define the pixels of Seq-Scope that are â¼0.5-0.8 µm apart from each other. From tissue sections, Seq-Scope visualizes spatial transcriptome heterogeneity at multiple histological scales, including tissue zonation according to the portal-central (liver), crypt-surface (colon) and inflammation-fibrosis (injured liver) axes, cellular components including single-cell types and subtypes, and subcellular architectures of nucleus and cytoplasm. Seq-Scope is quick, straightforward, precise, and easy-to-implement and makes spatial single-cell analysis accessible to a wide group of biomedical researchers.
Asunto(s)
Microscopía , Transcriptoma/genética , Animales , Núcleo Celular/genética , Colon/patología , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Inflamación/genética , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Mitocondrias/genética , ARN/metabolismo , Análisis de la Célula IndividualRESUMEN
Increasing evidence indicates that the brain regulates peripheral immunity, yet whether and how the brain represents the state of the immune system remains unclear. Here, we show that the brain's insular cortex (InsCtx) stores immune-related information. Using activity-dependent cell labeling in mice (FosTRAP), we captured neuronal ensembles in the InsCtx that were active under two different inflammatory conditions (dextran sulfate sodium [DSS]-induced colitis and zymosan-induced peritonitis). Chemogenetic reactivation of these neuronal ensembles was sufficient to broadly retrieve the inflammatory state under which these neurons were captured. Thus, we show that the brain can store and retrieve specific immune responses, extending the classical concept of immunological memory to neuronal representations of inflammatory information.
Asunto(s)
Inmunidad , Corteza Insular/fisiología , Neuronas/fisiología , Animales , Colitis/inducido químicamente , Colitis/complicaciones , Colitis/inmunología , Colon/patología , Sulfato de Dextran , Femenino , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Peritoneo/patología , Peritonitis/complicaciones , Peritonitis/inmunología , Peritonitis/patología , Sinapsis/metabolismo , ZimosanRESUMEN
The intestinal immune system interacts with commensal microbiota to maintain gut homeostasis. Furthermore, stress alters the microbiome composition, leading to impaired brain function; yet how the intestinal immune system mediates these effects remains elusive. Here we report that colonic γδ T cells modulate behavioral vulnerability to chronic social stress via dectin-1 signaling. We show that reduction in specific Lactobacillus species, which are involved in T cell differentiation to protect the host immune system, contributes to stress-induced social-avoidance behavior, consistent with our observations in patients with depression. Stress-susceptible behaviors derive from increased differentiation in colonic interleukin (IL)-17-producing γδ T cells (γδ17 T cells) and their meningeal accumulation. These stress-susceptible cellular and behavioral phenotypes are causally mediated by dectin-1, an innate immune receptor expressed in γδ T cells. Our results highlight the previously unrecognized role of intestinal γδ17 T cells in the modulation of psychological stress responses and the importance of dectin-1 as a potential therapeutic target for the treatment of stress-induced behaviors.
Asunto(s)
Intestinos , Lectinas Tipo C , Colon , Transducción de Señal , Receptores de Antígenos de Linfocitos T gamma-deltaRESUMEN
How the colon microenvironment confronts a breach of its epithelial border remains incompletely understood. In this issue, the laboratories of Lennon-Duménil and Vignjevic reveal a novel role for macrophages in sustaining epithelial integrity in the face of fungal metabolites.
Asunto(s)
Colon , Macrófagos , EpitelioRESUMEN
Endocannabinoids are host-derived lipid hormones that fundamentally impact gastrointestinal (GI) biology. The use of cannabis and other exocannabinoids as anecdotal treatments for various GI disorders inspired the search for mechanisms by which these compounds mediate their effects, which led to the discovery of the mammalian endocannabinoid system. Dysregulated endocannabinoid signaling was linked to inflammation and the gut microbiota. However, the effects of endocannabinoids on host susceptibility to infection has not been explored. Here, we show that mice with elevated levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG) are protected from enteric infection by Enterobacteriaceae pathogens. 2-AG directly modulates pathogen function by inhibiting virulence programs essential for successful infection. Furthermore, 2-AG antagonizes the bacterial receptor QseC, a histidine kinase encoded within the core Enterobacteriaceae genome that promotes the activation of pathogen-associated type three secretion systems. Taken together, our findings establish that endocannabinoids are directly sensed by bacteria and can modulate bacterial function.
Asunto(s)
Endocannabinoides/metabolismo , Enterobacteriaceae/patogenicidad , Animales , Ácidos Araquidónicos/química , Ácidos Araquidónicos/metabolismo , Adhesión Bacteriana , Proteínas Bacterianas/metabolismo , Sistemas de Secreción Bacterianos/metabolismo , Citrobacter rodentium/patogenicidad , Colon/microbiología , Colon/patología , Endocannabinoides/química , Infecciones por Enterobacteriaceae/microbiología , Femenino , Microbioma Gastrointestinal , Glicéridos/química , Glicéridos/metabolismo , Células HeLa , Interacciones Huésped-Patógeno , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Monoacilglicerol Lipasas/metabolismo , Salmonella/patogenicidad , VirulenciaRESUMEN
The precise mechanism by which oral infection contributes to the pathogenesis of extra-oral diseases remains unclear. Here, we report that periodontal inflammation exacerbates gut inflammation in vivo. Periodontitis leads to expansion of oral pathobionts, including Klebsiella and Enterobacter species, in the oral cavity. Amassed oral pathobionts are ingested and translocate to the gut, where they activate the inflammasome in colonic mononuclear phagocytes, triggering inflammation. In parallel, periodontitis results in generation of oral pathobiont-reactive Th17 cells in the oral cavity. Oral pathobiont-reactive Th17 cells are imprinted with gut tropism and migrate to the inflamed gut. When in the gut, Th17 cells of oral origin can be activated by translocated oral pathobionts and cause development of colitis, but they are not activated by gut-resident microbes. Thus, oral inflammation, such as periodontitis, exacerbates gut inflammation by supplying the gut with both colitogenic pathobionts and pathogenic T cells.
Asunto(s)
Colitis/patología , Enterobacter/fisiología , Microbioma Gastrointestinal , Klebsiella/fisiología , Boca/microbiología , Animales , Colitis/microbiología , Colon/microbiología , Colon/patología , Modelos Animales de Enfermedad , Enterobacter/aislamiento & purificación , Femenino , Inflamasomas/metabolismo , Interleucina-10/deficiencia , Interleucina-10/genética , Interleucina-1beta/metabolismo , Klebsiella/aislamiento & purificación , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodontitis/microbiología , Periodontitis/patología , Células Th17/citología , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
The colon is primarily responsible for absorbing fluids. It contains a large number of microorganisms including fungi, which are enriched in its distal segment. The colonic mucosa must therefore tightly regulate fluid influx to control absorption of fungal metabolites, which can be toxic to epithelial cells and lead to barrier dysfunction. How this is achieved remains unknown. Here, we describe a mechanism by which the innate immune system allows rapid quality check of absorbed fluids to avoid intoxication of colonocytes. This mechanism relies on a population of distal colon macrophages that are equipped with "balloon-like" protrusions (BLPs) inserted in the epithelium, which sample absorbed fluids. In the absence of macrophages or BLPs, epithelial cells keep absorbing fluids containing fungal products, leading to their death and subsequent loss of epithelial barrier integrity. These results reveal an unexpected and essential role of macrophages in the maintenance of colon-microbiota interactions in homeostasis. VIDEO ABSTRACT.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , Animales , Colon/metabolismo , Células Epiteliales/metabolismo , Epitelio , Femenino , Homeostasis , Inmunidad Innata/inmunología , Mucosa Intestinal/microbiología , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota , Transducción de SeñalRESUMEN
Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders.
Asunto(s)
Huesos/metabolismo , Colon/metabolismo , Motilidad Gastrointestinal/genética , Canales Iónicos/metabolismo , ARN/metabolismo , Serotonina/biosíntesis , Serotonina/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Huesos/citología , Calcio/metabolismo , Colitis/genética , Colitis/metabolismo , Colitis/prevención & control , Colon/fisiología , Heces/química , Femenino , Motilidad Gastrointestinal/fisiología , Células HEK293 , Humanos , Inmunohistoquímica , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Canales Iónicos/genética , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microbiota/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/metabolismo , Osteoclastos/metabolismo , Pirazinas/farmacología , ARN/farmacología , Ribonucleasa Pancreática/administración & dosificación , Serotonina/sangre , Serotonina/deficiencia , Tiadiazoles/farmacologíaRESUMEN
Interferon (IFN)-Is are crucial mediators of antiviral immunity and homeostatic immune system regulation. However, the source of IFN-I signaling under homeostatic conditions is unclear. We discovered that commensal microbes regulate the IFN-I response through induction of IFN-ß by colonic DCs. Moreover, the mechanism by which a specific commensal microbe induces IFN-ß was identified. Outer membrane (OM)-associated glycolipids of gut commensal microbes belonging to the Bacteroidetes phylum induce expression of IFN-ß. Using Bacteroides fragilis and its OM-associated polysaccharide A, we determined that IFN-ß expression was induced via TLR4-TRIF signaling. Antiviral activity of this purified microbial molecule against infection with either vesicular stomatitis virus (VSV) or influenza was demonstrated to be dependent on the induction of IFN-ß. In a murine VSV infection model, commensal-induced IFN-ß regulated natural resistance to virus infection. Due to the physiological importance of IFN-Is, discovery of an IFN-ß-inducing microbial molecule represents a potential approach for the treatment of some human diseases.
Asunto(s)
Inmunidad Innata , Microbiota , Virosis/microbiología , Animales , Bacteroides fragilis/fisiología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Colon/patología , Colon/virología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Glucolípidos/metabolismo , Inmunidad Innata/efectos de los fármacos , Interferón beta/sangre , Interferón beta/metabolismo , Masculino , Ratones Endogámicos C57BL , Microbiota/efectos de los fármacos , Polisacáridos Bacterianos/farmacología , Receptor Toll-Like 4/metabolismo , Vesiculovirus/fisiología , Virosis/genéticaRESUMEN
The enteric nervous system (ENS) coordinates diverse functions in the intestine but has eluded comprehensive molecular characterization because of the rarity and diversity of cells. Here we develop two methods to profile the ENS of adult mice and humans at single-cell resolution: RAISIN RNA-seq for profiling intact nuclei with ribosome-bound mRNA and MIRACL-seq for label-free enrichment of rare cell types by droplet-based profiling. The 1,187,535 nuclei in our mouse atlas include 5,068 neurons from the ileum and colon, revealing extraordinary neuron diversity. We highlight circadian expression changes in enteric neurons, show that disease-related genes are dysregulated with aging, and identify differences between the ileum and proximal/distal colon. In humans, we profile 436,202 nuclei, recovering 1,445 neurons, and identify conserved and species-specific transcriptional programs and putative neuro-epithelial, neuro-stromal, and neuro-immune interactions. The human ENS expresses risk genes for neuropathic, inflammatory, and extra-intestinal diseases, suggesting neuronal contributions to disease.
Asunto(s)
Sistema Nervioso Entérico/citología , Sistema Nervioso Entérico/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Neuronas/metabolismo , Cuerpos de Nissl/metabolismo , ARN Mensajero/metabolismo , Análisis de la Célula Individual/métodos , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Relojes Circadianos/genética , Colon/citología , Colon/metabolismo , Retículo Endoplásmico Rugoso/genética , Retículo Endoplásmico Rugoso/metabolismo , Retículo Endoplásmico Rugoso/ultraestructura , Células Epiteliales/metabolismo , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Íleon/citología , Íleon/metabolismo , Inflamación/genética , Inflamación/metabolismo , Enfermedades Intestinales/genética , Enfermedades Intestinales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/metabolismo , Neuroglía/citología , Neuroglía/metabolismo , Neuronas/citología , Cuerpos de Nissl/genética , Cuerpos de Nissl/ultraestructura , ARN Mensajero/genética , RNA-Seq , Ribosomas/metabolismo , Ribosomas/ultraestructura , Células del Estroma/metabolismoRESUMEN
The intestinal microbiota produces tens of thousands of metabolites. Here, we used host sensing of small molecules by G-protein coupled receptors (GPCRs) as a lens to illuminate bioactive microbial metabolites that impact host physiology. We screened 144 human gut bacteria against the non-olfactory GPCRome and identified dozens of bacteria that activated both well-characterized and orphan GPCRs, including strains that converted dietary histidine into histamine and shaped colonic motility; a prolific producer of the essential amino acid L-Phe, which we identified as an agonist for GPR56 and GPR97; and a species that converted L-Phe into the potent psychoactive trace amine phenethylamine, which crosses the blood-brain barrier and triggers lethal phenethylamine poisoning after monoamine oxidase inhibitor administration. These studies establish an orthogonal approach for parsing the microbiota metabolome and uncover multiple biologically relevant host-microbiota metabolome interactions.
Asunto(s)
Bacterias/crecimiento & desarrollo , Colon/microbiología , Microbioma Gastrointestinal/fisiología , Interacciones Microbiota-Huesped/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Células HEK293 , Humanos , RatonesRESUMEN
Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.
Asunto(s)
Colitis Ulcerosa/patología , Colon/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Bestrofinas/metabolismo , Antígenos CD8/metabolismo , Estudios de Casos y Controles , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon/patología , Enterocitos/citología , Enterocitos/metabolismo , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Interleucina-17/metabolismo , Masculino , Persona de Mediana Edad , Factores de Riesgo , Linfocitos T/citología , Linfocitos T/metabolismo , Trombospondinas/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
The colonic epithelium can undergo multiple rounds of damage and repair, often in response to excessive inflammation. The responsive stem cell that mediates this process is unclear, in part because of a lack of in vitro models that recapitulate key epithelial changes that occur in vivo during damage and repair. Here, we identify a Hopx+ colitis-associated regenerative stem cell (CARSC) population that functionally contributes to mucosal repair in mouse models of colitis. Hopx+ CARSCs, enriched for fetal-like markers, transiently arose from hypertrophic crypts known to facilitate regeneration. Importantly, we established a long-term, self-organizing two-dimensional (2D) epithelial monolayer system to model the regenerative properties and responses of Hopx+ CARSCs. This system can reenact the "homeostasis-injury-regeneration" cycles of epithelial alterations that occur in vivo. Using this system, we found that hypoxia and endoplasmic reticulum stress, insults commonly present in inflammatory bowel diseases, mediated the cyclic switch of cellular status in this process.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Colon/patología , Células Madre/patología , Células 3T3 , Animales , Colitis/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Proteínas de Homeodominio/metabolismo , Ratones , Modelos Biológicos , Oxígeno/farmacología , Regeneración/efectos de los fármacos , Células Madre/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacosRESUMEN
Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.
Asunto(s)
Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/terapia , Mucosa Intestinal/patología , Antígenos CD/metabolismo , Apirasa/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Muerte Celular/efectos de los fármacos , Microambiente Celular/efectos de los fármacos , Niño , Estudios de Cohortes , Colon/patología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Dipiridamol/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Predisposición Genética a la Enfermedad , Homeostasis/efectos de los fármacos , Humanos , Inmunoglobulina G/sangre , Memoria Inmunológica , Inflamación/patología , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/genética , Interferón Tipo I/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Metilprednisolona/farmacología , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismoRESUMEN
It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes are unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic but not bone marrow-derived macrophages, which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early-life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later-life susceptibility or resistance to iNKT cell-associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota, and they reveal an important postnatal function of macrophages that emerge in fetal life.
Asunto(s)
Colitis/inmunología , Mucosa Intestinal/inmunología , Listeriosis/inmunología , Macrófagos/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Animales , Proliferación Celular/genética , Colitis/microbiología , Colitis/patología , Colon/citología , Colon/embriología , Colon/inmunología , Colon/patología , Citocinas/metabolismo , Toxina Diftérica/administración & dosificación , Toxina Diftérica/inmunología , Modelos Animales de Enfermedad , Embrión de Mamíferos , Femenino , Microbioma Gastrointestinal/inmunología , Regulación del Desarrollo de la Expresión Génica/inmunología , Vida Libre de Gérmenes , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/embriología , Mucosa Intestinal/patología , Listeriosis/microbiología , Listeriosis/patología , Macrófagos/metabolismo , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , RNA-Seq , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.