RESUMEN
Innate lymphoid cells (ILCs) are critical in maintaining tissue homeostasis, and during infection and inflammation. Here we identify, by using combinatorial reporter mice, a rare ILC progenitor (ILCP) population, resident to the small intestinal lamina propria (siLP) in adult mice. Transfer of siLP-ILCP into recipients generates group 1 ILCs (including ILC1 and NK cells), ILC2s and ILC3s within the intestinal microenvironment, but almost exclusively group 1 ILCs in the liver, lung and spleen. Single cell gene expression analysis and high dimensional spectral cytometry analysis of the siLP-ILCPs and ILC progeny indicate that the phenotype of the group 1 ILC progeny is also influenced by the tissue microenvironment. Thus, a local pool of siLP-ILCP can contribute to pan-ILC generation in the intestinal microenvironment but has more restricted potential in other tissues, with a greater propensity than bone marrow-derived ILCPs to favour ILC1 and ILC3 production. Therefore, ILCP potential is influenced by both tissue of origin and the microenvironment during development. This may provide additional flexibility during the tuning of immune reactions.
Asunto(s)
Inmunidad Innata , Mucosa Intestinal , Células Progenitoras Linfoides , Ratones Endogámicos C57BL , Animales , Ratones , Mucosa Intestinal/inmunología , Mucosa Intestinal/citología , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/inmunología , Microambiente Celular/inmunología , Linfocitos/inmunología , Intestino Delgado/inmunología , Intestino Delgado/citología , Femenino , MasculinoRESUMEN
Inflammatory bowel diseases (IBDs) are chronic, relapsing, and inflammatory disorders of the gastrointestinal tract characterized by abnormal immune responses. Recently, STING has emerged as a promising therapeutic target for various autoinflammatory diseases. However, few STING-selective small molecules have been investigated as novel strategies for IBD. In this study, we sought to examine the effects of PROTAC-based STING degrader SP23 on acute colitis and explore its underlying mechanism. SP23 treatment notably alleviates dextran sulfate sodium (DSS)-induced colitis. Pharmacological degradation of STING significantly reduced the production of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, and inhibited macrophage polarization towards the M1 type. Furthermore, SP23 administration decreased the loss of tight junction proteins, including ZO-1, occludin, and claudin-1, and downregulated STING and NLRP3 signaling pathways in intestinal inflammation. In vitro, STING activated NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, which could be abrogated by SP23 and STING siRNA intervention. In conclusion, these findings provide new evidence for STING as a novel therapeutic target for IBD, and reveal that hyperactivation of STING could exaggerate colitis by inducing NLRP3/Caspase-1/GSDMD axis mediated intestinal epithelial cells pyroptosis.
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Colitis , Sulfato de Dextran , Macrófagos , Proteínas de la Membrana , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Piroptosis/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Transducción de Señal/efectos de los fármacos , Inflamasomas/metabolismo , Citocinas/metabolismo , Masculino , Humanos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/inmunología , Modelos Animales de Enfermedad , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
The gut barrier is essential for protection against pathogens and maintaining homeostasis. Macrophages are key players in the immune system, are indispensable for intestinal health, and contribute to immune defense and repair mechanisms. Understanding the multifaceted roles of macrophages can provide critical insights into maintaining and restoring gastrointestinal (GI) health. This review explores the essential role of macrophages in maintaining the gut barrier function and their contribution to post-inflammatory and post-infectious responses in the gut. Macrophages significantly contribute to gut barrier integrity through epithelial repair, immune modulation, and interactions with gut microbiota. They demonstrate active plasticity by switching phenotypes to resolve inflammation, facilitate tissue repair, and regulate microbial populations following an infection or inflammation. In addition, tissue-resident (M2) and infiltration (M1) macrophages convert to each other in gut problems such as IBS and IBD via major signaling pathways mediated by NF-κB, JAK/STAT, PI3K/AKT, MAPK, Toll-like receptors, and specific microRNAs such as miR-155, miR-29, miR-146a, and miR-199, which may be good targets for new therapeutic approaches. Future research should focus on elucidating the detailed molecular mechanisms and developing personalized therapeutic approaches to fully harness the potential of macrophages to maintain and restore intestinal permeability and gut health.
Asunto(s)
Microbioma Gastrointestinal , Inflamación , Macrófagos , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Inflamación/metabolismo , Inflamación/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/inmunología , Transducción de Señal , MicroARNs/genética , MicroARNs/metabolismo , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/metabolismo , PermeabilidadRESUMEN
IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.
Asunto(s)
Inmunidad Mucosa , Inmunoglobulina A , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Receptores de Leucotrieno B4 , Transducción de Señal , Animales , Metabolismo de los Lípidos/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Transducción de Señal/inmunología , Ratones , Receptores de Leucotrieno B4/metabolismo , Receptores de Leucotrieno B4/inmunología , Ácido Araquidónico/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Femenino , Microbioma Gastrointestinal/inmunología , Ratones NoqueadosRESUMEN
Intestinal macrophages play a key role in regulating immune tolerance in the gut. In this issue of Immunity, Mertens et al. uncover a mechanism for the establishment of memory in macrophage tolerance in the gut involving a bistable metabolic switch in macrophages and an intercellular positive feedback between macrophages and intestinal epithelial cells (IECs).
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Tolerancia Inmunológica , Mucosa Intestinal , Macrófagos , Macrófagos/inmunología , Tolerancia Inmunológica/inmunología , Humanos , Animales , Mucosa Intestinal/inmunología , Retroalimentación Fisiológica , Intestinos/inmunología , Células Epiteliales/inmunologíaRESUMEN
Chemokine receptors are essential for the immune response in the oral and gut mucosa. The gastrointestinal mucosa is characterized by the presence of immune populations because it is susceptible to inflammatory and infectious diseases, necessitating immune surveillance. Chemokine receptors are expressed on immune cells and play a role in gastrointestinal tissue-homing, although other non-immune cells also express them for various biological functions. CCR9, CXCR3 and CXCR6 play an important role in the T cell response in inflammatory and neoplastic conditions of the gastrointestinal mucosa. However, CXCR6 could also be found in gastric cancer cells, highlighting the different roles of chemokine receptors in different pathologies. On the other hand, CCR4 and CCR8 are critical for Treg migration in gastrointestinal tissues, correlating with poor prognosis in mucosal cancers. Other chemokine receptors are also important in promoting myeloid infiltration with context-dependent roles. Further, CXCR4 and CXCR7 are also present in gastrointestinal tumor cells and are known to stimulate proliferation, migration, and invasion into other tissues, among other pro-tumorigenic functions. Determining the processes underlying mucosal immunity and creating tailored therapeutic approaches for gastrointestinal diseases requires an understanding of the complex interactions that occur between chemokine receptors and their ligands in these mucosal tissues.
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Receptores de Quimiocina , Humanos , Receptores de Quimiocina/metabolismo , Animales , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/inmunologíaRESUMEN
Immune memory has been expanded to group 2 innate lymphoid cells (ILC2s), but the cellular and molecular bases remain incompletely understood. Based on house dust mite (HDM)-induced mice asthma models and human samples, we applied flow cytometry, parabiosis, in vivo imaging and adoptive transplantation to confirm the persistence, migration and function of CD45+lineage-CD90.2+NK1.1-NKp46-ST2-KLRG1+IL-17RB+ memory-like ILC2s (ml-ILC2s). Regulated by CCR9/CCL25 and S1P signaling, ml-ILC2s reside in the lamina propria of small intestines (siLP) in asthma remission, and subsequently move to airway upon re-encountering antigens or alarmins. Furthermore, ml-ILC2s possess properties of longevity, potential of rapid proliferation and producing IL-13, and display transcriptional characteristics with up-regulation of Tox and Tcf-7. ml-ILC2s transplantation restore the asthmatic changes abrogated by Tox and Tcf7 knockdown. Our data identify siLP ml-ILC2s as a memory-like subset, which promotes asthma relapse. Targeting TCF-1 and TOX might be promising for preventing asthma recurrence.
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Asma , Factor Nuclear 1-alfa del Hepatocito , Proteínas de Homeodominio , Inmunidad Innata , Memoria Inmunológica , Linfocitos , Animales , Femenino , Humanos , Masculino , Ratones , Traslado Adoptivo , Asma/inmunología , Modelos Animales de Enfermedad , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Interleucina-13/metabolismo , Interleucina-13/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/metabolismo , Intestinos/inmunología , Intestinos/patología , Linfocitos/inmunología , Ratones Endogámicos C57BL , Pyroglyphidae/inmunología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismoRESUMEN
The intestine exhibits distinct characteristics along its length, with a substantial immune cell reservoir and diverse microbiota crucial for maintaining health. This study investigates how anatomical location and regional microbiota influence intestinal immune cell abundance. Using conventionally colonized and germ-free mice, segment-specific immune cell composition and microbial communities were assessed. Metagenomic sequencing analyzed microbiome variations, while flow cytometry and immunofluorescence examined immune cell composition. Microbiome composition varied significantly along the intestine, with diversity and abundance increasing from upper to lower segments. Immune cells showed distinct segment-specific patterning influenced by microbial colonization and localization. T cell subsets displayed varied dependence on microbiome presence and anatomical location. This study highlights locoregional differences in intestinal immune cell and microbiome composition, identifying immune subsets susceptible to microbiota presence. The findings provide context for understanding immune cell alterations in disease models.
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Bacterias , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Animales , Ratones , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/inmunología , Intestinos/microbiología , Intestinos/inmunología , Intestinos/citología , Metagenómica , Vida Libre de Gérmenes , Femenino , Subgrupos de Linfocitos T/inmunología , Masculino , Mucosa Intestinal/microbiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/citologíaRESUMEN
Introduction: Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown. Methods: To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses. Results: Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation. Discussion: Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease.
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Citrobacter rodentium , Colitis , Infecciones por Enterobacteriaceae , Inmunidad Innata , Interleucina-22 , Interleucinas , Linfocitos , Ratones Noqueados , Sirtuinas , Animales , Ratones , Linfocitos/inmunología , Linfocitos/metabolismo , Interleucinas/metabolismo , Interleucinas/inmunología , Interleucinas/genética , Sirtuinas/genética , Sirtuinas/metabolismo , Colitis/inmunología , Colitis/inducido químicamente , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Ratones Endogámicos C57BL , Sulfato de Dextran , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: This study will explore the function of WTAP, the critical segment of m6A methyltransferase complex, in UC and its regulation on immune response. METHODS: The expression levels of key proteins were detected in colon tissues which were derived from UC patients and mice. Macrophage polarization and CD4+ T cell infiltration were detected by flow cytometry and IF staining. ELISA assay was utilized to analyze the level of the inflammatory cytokines. m6A-RIP-PCR, actinomycin D test, and RIP assays were utilized to detect the m6A level, stability, and bound proteins of CES2 mRNA. A dual luciferase reporter assay was conducted to confirm the transcriptional interactions between genes. A co-culture system of intestinal epithelium-like organs was constructed to detect the primary mouse intestinal epithelial cells (PMIEC) differentiation. The interaction between proteins was detected via Co-IP assay. RESULTS: The expression of WTAP and CES2 in UC tissues was increased and decreased, respectively. Knockdown of WTAP inhibited the progression of UC in mice by inhibiting M1 macrophage polarization and CD4+ T cell infiltration. WTAP combined YTHDF2 to promote the m6A modification of CES2 mRNA and inhibited its expression. CES2 co-expressed with EPHX2 and overexpression of CES2 promoted the differentiation of PMIEC. The inhibitory effect of WTAP knockdown on the progress of UC was partially abrogated by CES2 knockdown. CONCLUSION: WTAP/YTHDF2 silences CES2 by promoting its m6A modification and then promotes the progression of UC. WTAP could be a promoting therapy target of UC.
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Colitis Ulcerosa , Progresión de la Enfermedad , Macrófagos , Animales , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Ratones , Humanos , Macrófagos/metabolismo , Macrófagos/inmunología , Modelos Animales de Enfermedad , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/inmunología , Masculino , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Regulación de la Expresión Génica , Metiltransferasas/metabolismo , Metiltransferasas/genética , FemeninoRESUMEN
In 2012, the Strategic Advisory Group of Experts on Immunization (SAGE) recommended introduction of at least one inactivated poliovirus vaccine (IPV) dose in essential immunization programs. We evaluated systemic humoral and intestinal mucosal immunity of a sequential IPV-bivalent oral poliovirus vaccine (bOPV) schedule compared with a co-administration IPV + bOPV schedule in an open-label, randomized, controlled, non-inferiority, inequality trial in Dhaka, Bangladesh. Healthy infants aged 6 weeks were randomized to either: (A) IPV and bOPV at 6 and bOPV at 10 and 14 weeks (IPV + bOPV-bOPV-bOPV); or (B) IPV at 6 and bOPV at 10 and 14 weeks (IPV-bOPV-bOPV). Of 456 participants enrolled and randomly assigned during May-August 2015, 428 (94%) were included in the modified intention-to-treat analysis (arm A: 211, arm B: 217). Humoral immune responses did not differ at 18 weeks between study arms: type 1 (98% versus 96%; p = 0.42), type 2 (37% versus 39%; p = 0.77), and type 3 (97% versus 93%; p = 0.07). Virus shedding one week after the bOPV challenge dose in arm B was non-inferior to arm A (type 1 difference = -3% [90% confidence interval: -6 - 0.4%]; type 3 difference: -3% [-6 to -0.2%]). Twenty-six adverse events including seven serious adverse events were reported among 25 participants including one death; none were attributed to study vaccines. An IPV-bOPV-bOPV sequential schedule induced comparable systemic humoral immunity to all poliovirus types and types 1 and 3 intestinal mucosal immunity as an IPV + bOPV-bOPV-bOPV co-administration schedule.
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Anticuerpos Antivirales , Inmunidad Humoral , Inmunidad Mucosa , Esquemas de Inmunización , Poliomielitis , Vacuna Antipolio de Virus Inactivados , Vacuna Antipolio Oral , Humanos , Vacuna Antipolio de Virus Inactivados/inmunología , Vacuna Antipolio de Virus Inactivados/administración & dosificación , Vacuna Antipolio de Virus Inactivados/efectos adversos , Vacuna Antipolio Oral/administración & dosificación , Vacuna Antipolio Oral/inmunología , Vacuna Antipolio Oral/efectos adversos , Bangladesh , Masculino , Femenino , Lactante , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Poliomielitis/prevención & control , Poliomielitis/inmunología , Poliovirus/inmunología , Mucosa Intestinal/inmunologíaRESUMEN
Dihydromyricetin (DMY), a natural flavonoid compound, are believed to prevent inflammatory response, dealing with pathogens and repairing the intestinal barrier. The objective of this study was to investigate whether DMY supplementation could attenuate intestinal damage in the context of enterotoxigenic Escherichia coli K88 (ETEC F4+) infection. After weaning, different litters of pigs were randomly assigned to one of the following treatments: (1) non-challenged control (CON, fed with basal diet); (2) ETEC-challenged control (ECON, fed with basal diet); and (3) ETEC challenge + DMY treatment (EDMY, fed with basal diet plus 300 mg kg-1 DMY). We observed a significant reduction in fecal Escherichia coli shedding and diarrhea incidence, but an increase in ADG in pigs of EDMY group compared to the pigs of ECON group. Relative to the pigs of ECON group, dietary DMY treatment decreased (P < 0.05) concentrations of the serum D-xylose, D-lactate and diamine oxidase (DAO), but increased the abundance of zonula occludens-1 (ZO-1) in the jejunum of pigs. In addition, DMY also decreased (P < 0.05) the number of S-phase cells and the percentage of total apoptotic epithelial cells of jejunal epithelium in pigs of the EDMY group compared to the pigs of the ECON group. Furthermore, DMY decreased the mRNA expression levels of critical immune-associated genes TLR4, NFκB, Caspase3, Caspase9, IL-1ß, IL-6, TNF-α and the protein p-NFκB and p-IκBα expressions of intestinal epithelium in pigs of the EDMY group compared to the pigs of the ECON group. Compared to the ECON group, DMY elevated (P < 0.05) the expression levels of ß-defensins PBD1, PBD2, PBD3, PBD129, as well as the abundance of secreted IgA in intestinal mucosae of the EDMY group. Thus, our results indicate that DMY may relieve intestinal integrity damage due to Escherichia coli F4.
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Escherichia coli Enterotoxigénica , Infecciones por Escherichia coli , Flavonoles , Mucosa Intestinal , Enfermedades de los Porcinos , Animales , Escherichia coli Enterotoxigénica/efectos de los fármacos , Porcinos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/inmunología , Flavonoles/farmacología , Flavonoles/uso terapéutico , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/veterinaria , Infecciones por Escherichia coli/inmunología , Enfermedades de los Porcinos/tratamiento farmacológico , Enfermedades de los Porcinos/microbiología , Enfermedades de los Porcinos/inmunología , Destete , Citocinas/metabolismo , Diarrea/tratamiento farmacológico , Diarrea/veterinaria , Apoptosis/efectos de los fármacos , Proteína de la Zonula Occludens-1/metabolismo , Proteína de la Zonula Occludens-1/genéticaRESUMEN
A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-ß (TGF-ß)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging.
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Envejecimiento , Homeostasis , Inmunoglobulina A , Ratones Endogámicos BALB C , Condicionamiento Físico Animal , Animales , Inmunoglobulina A/metabolismo , Inmunoglobulina A/inmunología , Ratones , Envejecimiento/inmunología , Citocinas/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Factor Activador de Células B/metabolismo , Factor Activador de Células B/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Intestino Delgado/inmunología , Intestino Delgado/metabolismo , Masculino , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genéticaRESUMEN
PROBLEM: There is a higher incidence of irritable bowel syndrome with miscarriages, and recurrent miscarriages of otherwise normal embryos have been linked to subnormal expression of the immune checkpoint inhibitor CD200L. We sought to determine if alterations in the expression of the CD200 immune checkpoint inhibitor occur in colonic tissue in IBS-D patients. METHOD OF STUDY: Quantitative immunohistochemical staining of biopsies from proximal and distal colon or rectum for the inhibitory CD200L and CD200S molecules was done. CD56 cells were also enumerated as they play a role in recurrent miscarriages and may express CD200S. RESULTS: CD200L was decreased and CD200S was unchanged in epithelium but not stroma of 3 IBS-D cases. One case had an increase in both CD200L and CD200S. CD56 cells were also stained for CD200S. Degranulation was assessed by the percentage of extracellular CD200S that was increased as epithelial CD200L decreased. CONCLUSIONS: This pilot study was promising and warrants a larger sample to determine if a correlation between uterine implantation site CD200L and CD200S expression in normal and failing implantation sites is needed. Colonic epithelial CD200L may then provide useful information about the pathogenesis of the spontaneous miscarriage in individual cases.
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Aborto Habitual , Antígenos CD , Diarrea , Síndrome del Colon Irritable , Humanos , Femenino , Síndrome del Colon Irritable/inmunología , Síndrome del Colon Irritable/metabolismo , Aborto Habitual/inmunología , Aborto Habitual/metabolismo , Antígenos CD/metabolismo , Adulto , Diarrea/inmunología , Embarazo , Proyectos Piloto , Tolerancia Inmunológica , Transducción de Señal , Antígeno CD56/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Colon/patología , Colon/inmunología , Colon/metabolismoRESUMEN
The intimate relationship between the epithelium and immune system is crucial for maintaining tissue homeostasis, with perturbations therein linked to autoimmune disease and cancer1-3. Whereas stem cell-derived organoids are powerful models of epithelial function4, they lack tissue-resident immune cells that are essential for capturing organ-level processes. We describe human intestinal immuno-organoids (IIOs), formed through self-organization of epithelial organoids and autologous tissue-resident memory T (TRM) cells, a portion of which integrate within the epithelium and continuously survey the barrier. TRM cell migration and interaction with epithelial cells was orchestrated by TRM cell-enriched transcriptomic programs governing cell motility and adhesion. We combined IIOs and single-cell transcriptomics to investigate intestinal inflammation triggered by cancer-targeting biologics in patients. Inflammation was associated with the emergence of an activated population of CD8+ T cells that progressively acquired intraepithelial and cytotoxic features. The appearance of this effector population was preceded and potentiated by a T helper-1-like CD4+ population, which initially produced cytokines and subsequently became cytotoxic itself. As a system amenable to direct perturbation, IIOs allowed us to identify the Rho pathway as a new target for mitigation of immunotherapy-associated intestinal inflammation. Given that they recapitulate both the phenotypic outcomes and underlying interlineage immune interactions, IIOs can be used to study tissue-resident immune responses in the context of tumorigenesis and infectious and autoimmune diseases.
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Intestinos , Organoides , Femenino , Humanos , Masculino , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/citología , Movimiento Celular/inmunología , Células Epiteliales/inmunología , Células Epiteliales/citología , Inmunoterapia/efectos adversos , Inflamación/inmunología , Inflamación/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/citología , Intestinos/inmunología , Intestinos/citología , Células T de Memoria/citología , Células T de Memoria/inmunología , Organoides/citología , Organoides/inmunología , Análisis de la Célula Individual , Transcriptoma , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más AñosRESUMEN
Zymogen granule 16 (ZG16) is a secretory glycoprotein found in zymogen granules, which also plays an important role in colorectal inflammation and cancer. Herein, a ZG16 gene knock-out (ZG16-/-) mouse line was established and we found that ZG16 deletion damaged the intestinal mucosal barrier and gut microbiota, which resulted in low-level inflammation and further promoted the development of ulcerative colitis and inflammation-related colorectal cancer. Meanwhile, a metabolomics analysis on mouse feces showed that the metabolites significantly differed between ZG16-/- and WT mice, which were important mediators of host-microbiota communication and may impact the pulmonary inflammation of mice. Indeed, ZG16-/- mice showed more severe inflammation in a bronchial asthma model. Taken together, the results demonstrate that ZG16 plays a pivotal role in inhibiting inflammation and regulating immune responses in colorectum and lung of experimental animals, which may provide a better understanding of the underlying mechanism of human inflammatory diseases associated with ZG16.
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Microbioma Gastrointestinal , Mucosa Intestinal , Ratones Endogámicos C57BL , Ratones Noqueados , Animales , Microbioma Gastrointestinal/inmunología , Ratones , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Asma/inmunología , Asma/metabolismo , Asma/microbiología , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Colitis Ulcerosa/metabolismo , Humanos , Pulmón/inmunología , Pulmón/patología , Pulmón/metabolismo , Modelos Animales de Enfermedad , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Masculino , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Bacterias/metabolismo , Bacterias/inmunología , Glicoproteínas/metabolismo , Glicoproteínas/genéticaRESUMEN
The functions of the natural dsRNA sensors TLR3 (TRIF) and RIG-I (MAVS) are crucial during viral challenge and have not been accurately clarified in adaptive immune responses to rotavirus (RV) infection. In this study, we found that RV infection caused severe pathological damage to the small intestine of TLR3-/- and TRIF-/- mice. Our data found that dendritic cells from TLR3-/- and TRIF-/- mice had impaired Ag presentation to the RV and attenuated initiation of T cells upon viral infection. These attenuated functions resulted in impaired CD4+ T and CD8+ T function in mice lacking TLR3-TRIF signaling postinfection. Additionally, attenuated proliferative capacity of T cells from TLR3-/- and TRIF-/- mice was observed. Subsequently, we observed a significant reduction in the absolute number of memory T cells in the spleen and mesenteric lymph node (MLN) of TRIF-/- recipient mice following RV infection in a bone marrow chimeric model. Furthermore, there was reduced migration of type 2 classical dendritic cells from the intestine to MLNs after RV infection in TLR3-/- and TRIF-/- mice. Notably, RV infection resulted in attenuated killing of spleen and MLN tissues in TRIF-/- and MAVS-/- mice. Finally, we demonstrated that RV infection promoted apoptosis of CD8+ T cells in TRIF-/- and TLR3-/-MAVS-/- mice. Taken together, our findings highlight an important mechanism of TLR3 signaling through TRIF in mucosal T cell responses to RV and lay the foundation for the development of a novel vaccine.
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Proteínas Adaptadoras Transductoras de Señales , Proteínas Adaptadoras del Transporte Vesicular , Células Dendríticas , Ratones Noqueados , Infecciones por Rotavirus , Rotavirus , Transducción de Señal , Receptor Toll-Like 3 , Animales , Receptor Toll-Like 3/inmunología , Ratones , Infecciones por Rotavirus/inmunología , Transducción de Señal/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Rotavirus/inmunología , Células Dendríticas/inmunología , Ratones Endogámicos C57BL , Mucosa Intestinal/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunidad Mucosa , Presentación de Antígeno/inmunologíaRESUMEN
Ectodermal mesenchymal stem cells-derived conditioned medium (EMSCs-CM) has been reported to protect against ulcerative colitis (UC) in mice, but its underlying mechanism in alleviating UC need to be further elucidated. Here, it is reported that EMSCs-CM could attenuate pro-inflammatory response of LPS-induced IEC-6 cells and regulate the polarization of macrophages towards anti-inflammatory type in vitro. Furthermore, PLGA microspheres prepared by the double emulsion method were constructed for oral delivery of EMSCs-CM (EMSCs-CM-PLGA), which are beneficial for colon-targeted adhesion of EMSCs-CM to the damaged colon mucosa. The results showed that orally-administered of EMSCs-CM-PLGA microspheres reduced inflammatory cells infiltration and maintained the intestinal mucosal barrier. Further investigation found that EMSCs-CM-PLGA microspheres treatment gradually inhibited the activation of NF-κB pathway to regulate M1/M2 polarization balance in colon tissue macrophages, thereby alleviating DSS-induced UC. These results of this study will provide a theoretical basis for clinical application of EMSCs-CM in UC repair.
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Colitis Ulcerosa , Macrófagos , Células Madre Mesenquimatosas , Microesferas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Animales , Colitis Ulcerosa/terapia , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Medios de Cultivo Condicionados/farmacología , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Ratones , Colon/patología , Colon/efectos de los fármacos , FN-kappa B/metabolismo , Sulfato de Dextran , Masculino , Línea Celular , Mucosa Intestinal/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Modelos Animales de Enfermedad , Ratas , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Ratones Endogámicos C57BL , HumanosRESUMEN
Sepsis-induced intestinal injury is a common complication that increases the morbidity and mortality associated with sepsis. UCP2, a mitochondrial membrane protein, is involved in numerous cellular processes, including metabolism, inflammation, and pyroptosis. According to our previous studies, UCP2 expression increases in septic intestinal tissue. However, its function in intestinal damage is not known. This work investigated UCP2's role in intestinal injury caused by sepsis. A sepsis mouse model was established in wild-type and UCP2-knockout (UCP2-KO) animals using cecal ligation and puncture (CLP). MCC950, an NLRP3 inflammasome inhibitor, was injected intraperitoneally 3 h before CLP surgery. Overall, significantly higher levels of UCP2 were observed in the intestines of septic mice. UCP2-KO mice subjected to CLP exhibited exacerbated intestinal damage, characterized by enhanced mucosal erosion, inflammatory cell infiltration, and increased intestinal permeability. Furthermore, UCP2 knockout significantly increased oxidative stress, inflammation, and pyroptosis in the CLP mouse intestines. Interestingly, MCC950 not only inhibited pyroptosis but also reversed inflammation, oxidative stress as well as damage to intestinal tissues as a result of UCP2 knockout. Our results highlighted the protective functions of UCP2 in sepsis-associated intestinal injury through modulation of inflammation and oxidative stress via NLRP3 inflammasome-induced pyroptosis.