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1.
Annu Rev Immunol ; 38: 23-48, 2020 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-32340570

RESUMEN

The gastrointestinal tract harbors numerous commensal bacteria, referred to as the microbiota, that benefit host health by digesting dietary components and eliminating pathogens. The intestinal microbiota maintains epithelial barrier integrity and shapes the mucosal immune system, balancing host defense and oral tolerance with microbial metabolites, components, and attachment to host cells. To avoid aberrant immune responses, epithelial cells segregate the intestinal microbiota from immune cells by constructing chemical and physical barriers, leading to the establishment of host-commensal mutualism. Furthermore, intestinal immune cells participate in the maintenance of a healthy microbiota community and reinforce epithelial barrier functions. Perturbations of the microbiota composition are commonly observed in patients with autoimmune diseases and chronic inflammatory disorders. An understanding of the intimate interactions between the intestinal microbiota, epithelial cells, and immune cells that are crucial for the maintenance of intestinal homeostasis might promote advances in diagnostic and therapeutic approaches for various diseases.


Asunto(s)
Microbioma Gastrointestinal/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Animales , Susceptibilidad a Enfermedades , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/metabolismo
2.
Nature ; 629(8013): 901-909, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38658756

RESUMEN

The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1-5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.


Asunto(s)
Colangitis Esclerosante , Microbioma Gastrointestinal , Inflamación , Hígado , Macrófagos , Enfermedad del Hígado Graso no Alcohólico , Simbiosis , Animales , Femenino , Humanos , Masculino , Ratones , Bacteroidetes/metabolismo , Colangitis Esclerosante/inmunología , Colangitis Esclerosante/microbiología , Colangitis Esclerosante/patología , Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Perfilación de la Expresión Génica , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Interleucina-10/inmunología , Interleucina-10/metabolismo , Hígado/inmunología , Hígado/patología , Hígado/microbiología , Macrófagos/citología , Macrófagos/inmunología , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/microbiología , Enfermedad del Hígado Graso no Alcohólico/patología , Vena Porta , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/metabolismo , Análisis de la Célula Individual , Simbiosis/inmunología
3.
Immunity ; 50(3): 549-551, 2019 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-30893585

RESUMEN

In a recent issue of Cell, Mayassi et al. (2019) show that chronic inflammation in celiac disease (CeD) patients changes the repertoire and functional phenotype of intestinal TCR γδ+ intraepithelial lymphocytes. These changes are not reversed by gluten-free dietary regimens, suggesting that they might underlie the long-term sensitivity of CeD patients to gluten.


Asunto(s)
Enfermedad Celíaca , Glútenes , Humanos , Inflamación , Intestinos , Linfocitos
4.
Proc Natl Acad Sci U S A ; 121(16): e2313070121, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38588434

RESUMEN

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) is characterized by amyopathic DM with interstitial lung disease (ILD). Patients with anti-MDA5 antibody-associated ILD frequently develop rapidly progression and present high mortality rate in the acute phase. Here, we established a murine model of ILD mediated by autoimmunity against MDA5. Mice immunized with recombinant murine MDA5 whole protein, accompanied with complete Freund's adjuvant once a week for four times, developed MDA5-reactive T cells and anti-MDA5 antibodies. After acute lung injury induced by intranasal administration of polyinosinic-polycytidylic acid [poly (I:C)] mimicking viral infection, the MDA5-immunized mice developed fibrotic ILD representing prolonged respiratory inflammation accompanied by fibrotic changes 2 wk after poly (I:C)-administration, while the control mice had quickly and completely recovered from the respiratory inflammation. Treatment with anti-CD4 depleting antibody, but not anti-CD8 depleting antibody, suppressed the severity of MDA5-induced fibrotic ILD. Upregulation of interleukin (IL)-6 mRNA, which was temporarily observed in poly (I:C)-treated mice, was prolonged in MDA5-immunized mice. Treatment with anti-IL-6 receptor antibody ameliorated the MDA5-induced fibrotic ILD. These results suggested that autoimmunity against MDA5 exacerbates toll-like receptor 3-mediated acute lung injury, and prolongs inflammation resulting in the development of fibrotic ILD. IL-6 may play a key role initiating ILD in this model.


Asunto(s)
Lesión Pulmonar Aguda , Dermatomiositis , Enfermedades Pulmonares Intersticiales , Melanoma , Humanos , Animales , Ratones , Dermatomiositis/diagnóstico , Dermatomiositis/complicaciones , Pronóstico , Progresión de la Enfermedad , Autoinmunidad , Helicasa Inducida por Interferón IFIH1/genética , Autoanticuerpos , Enfermedades Pulmonares Intersticiales/diagnóstico , Interleucina-6 , Inflamación/complicaciones , Estudios Retrospectivos
5.
Immunity ; 47(6): 1182-1196.e10, 2017 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-29262351

RESUMEN

CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/inmunología , Ácidos y Sales Biliares/inmunología , Linfocitos T CD4-Positivos/inmunología , Enfermedad de Crohn/inmunología , Ileítis/inmunología , Mucosa Intestinal/inmunología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Acridinas/farmacología , Adulto , Animales , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/farmacología , Transporte Biológico , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/patología , Enfermedad de Crohn/genética , Enfermedad de Crohn/patología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Homeostasis/inmunología , Humanos , Ileítis/genética , Ileítis/patología , Íleon/inmunología , Íleon/patología , Inmunidad Mucosa , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Estrés Oxidativo , Transducción de Señal , Tetrahidroisoquinolinas/farmacología
6.
Int Immunol ; 36(4): 155-166, 2024 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-38108401

RESUMEN

Ulcerative colitis (UC) is a chronic disorder of the large intestine with inflammation and ulceration. The incidence and prevalence of UC have been rapidly increasing worldwide, but its etiology remains unknown. In patients with UC, the accumulation of eosinophils in the large intestinal mucosa is associated with increased disease activity. However, the molecular mechanism underlying the promotion of intestinal eosinophilia in patients with UC remains poorly understood. Here, we show that uridine diphosphate (UDP)-glucose mediates the eosinophil-dependent promotion of colonic inflammation via the purinergic receptor P2Y14. The expression of P2RY14 mRNA was upregulated in the large intestinal mucosa of patients with UC. The P2Y14 receptor ligand UDP-glucose was increased in the large intestinal tissue of mice administered dextran sodium sulfate (DSS). In addition, P2ry14 deficiency and P2Y14 receptor blockade mitigated DSS-induced colitis. Among the large intestinal immune cells and epithelial cells, eosinophils highly expressed P2ry14 mRNA. P2ry14-/- mice transplanted with wild-type bone marrow eosinophils developed more severe DSS-induced colitis compared with P2ry14-/- mice that received P2ry14-deficient eosinophils. UDP-glucose prolonged the lifespan of eosinophils and promoted gene transcription in the cells through P2Y14 receptor-mediated activation of ERK1/2 signaling. Thus, the UDP-glucose/P2Y14 receptor axis aggravates large intestinal inflammation by accelerating the accumulation and activation of eosinophils.


Asunto(s)
Colitis Ulcerosa , Eosinofilia , Humanos , Ratones , Animales , Uridina Difosfato Glucosa/farmacología , Eosinófilos , Inflamación , Mucosa Intestinal , ARN Mensajero , Glucosa/efectos adversos , Sulfato de Dextran , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad
7.
Nature ; 566(7742): 110-114, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30675063

RESUMEN

Small intestinal mononuclear cells that express CX3CR1 (CX3CR1+ cells) regulate immune responses1-5. CX3CR1+ cells take up luminal antigens by protruding their dendrites into the lumen1-4,6. However, it remains unclear how dendrite protrusion by CX3CR1+ cells is induced in the intestine. Here we show in mice that the bacterial metabolites pyruvic acid and lactic acid induce dendrite protrusion via GPR31 in CX3CR1+ cells. Mice that lack GPR31, which was highly and selectively expressed in intestinal CX3CR1+ cells, showed defective dendrite protrusions of CX3CR1+ cells in the small intestine. A methanol-soluble fraction of the small intestinal contents of specific-pathogen-free mice, but not germ-free mice, induced dendrite extension of intestinal CX3CR1+ cells in vitro. We purified a GPR31-activating fraction, and identified lactic acid. Both lactic acid and pyruvic acid induced dendrite extension of CX3CR1+ cells of wild-type mice, but not of Gpr31b-/- mice. Oral administration of lactate and pyruvate enhanced dendrite protrusion of CX3CR1+ cells in the small intestine of wild-type mice, but not in that of Gpr31b-/- mice. Furthermore, wild-type mice treated with lactate or pyruvate showed an enhanced immune response and high resistance to intestinal Salmonella infection. These findings demonstrate that lactate and pyruvate, which are produced in the intestinal lumen in a bacteria-dependent manner, contribute to enhanced immune responses by inducing GPR31-mediated dendrite protrusion of intestinal CX3CR1+ cells.


Asunto(s)
Bacterias/metabolismo , Receptor 1 de Quimiocinas CX3C/metabolismo , Extensiones de la Superficie Celular/metabolismo , Intestino Delgado/citología , Intestino Delgado/microbiología , Ácido Láctico/metabolismo , Ácido Pirúvico/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Bacterias/inmunología , Receptor 1 de Quimiocinas CX3C/deficiencia , Receptor 1 de Quimiocinas CX3C/genética , Extensiones de la Superficie Celular/efectos de los fármacos , Extensiones de la Superficie Celular/inmunología , Femenino , Células HEK293 , Humanos , Intestino Delgado/efectos de los fármacos , Intestino Delgado/inmunología , Ácido Láctico/farmacología , Lactobacillus helveticus/metabolismo , Masculino , Metanol , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ácido Pirúvico/farmacología , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Salmonella/inmunología , Salmonella/metabolismo
8.
Eur J Immunol ; 53(8): e2249866, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37191284

RESUMEN

The intestinal tract harbors diverse microorganisms, host- and microbiota-derived metabolites, and potentially harmful dietary antigens. The epithelial barrier separates the mucosa, where diverse immune cells exist, from the lumen to avoid excessive immune reactions against microbes and dietary antigens. Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, is characterized by a chronic and relapsing disorder of the gastrointestinal tract. Although the precise etiology of IBD is still largely unknown, accumulating evidence suggests that IBD is multifactorial, involving host genetics and microbiota. Alterations in the metabolomic profiles and microbial community are features of IBD. Advances in mass spectrometry-based lipidomic technologies enable the identification of changes in the composition of intestinal lipid species in IBD. Because lipids have a wide range of functions, including signal transduction and cell membrane formation, the dysregulation of lipid metabolism drastically affects the physiology of the host and microorganisms. Therefore, a better understanding of the intimate interactions of intestinal lipids with host cells that are implicated in the pathogenesis of intestinal inflammation might aid in the identification of novel biomarkers and therapeutic targets for IBD. This review summarizes the current knowledge on the mechanisms by which host and microbial lipids control and maintain intestinal health and diseases.


Asunto(s)
Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Colitis Ulcerosa/metabolismo , Intestinos , Lípidos , Mucosa Intestinal
9.
Immunity ; 42(2): 279-293, 2015 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-25692702

RESUMEN

Crosslinking of the immunoglobulin receptor FcεRI activates basophils and mast cells to induce immediate and chronic allergic inflammation. However, it remains unclear how the chronic allergic inflammation is regulated. Here, we showed that ecto-nucleotide pyrophosphatase-phosphodiesterase 3 (E-NPP3), also known as CD203c, rapidly induced by FcεRI crosslinking, negatively regulated chronic allergic inflammation. Basophil and mast cell numbers increased in Enpp3(-/-) mice with augmented serum ATP concentrations. Enpp3(-/-) mice were highly sensitive to chronic allergic pathologies, which was reduced by ATP blockade. FcεRI crosslinking induced ATP secretion from basophils and mast cells, and ATP activated both cells. ATP clearance was impaired in Enpp3(-/-) cells. Enpp3(-/-)P2rx7(-/-) mice showed decreased responses to FcεRI crosslinking. Thus, ATP released by FcεRI crosslinking stimulates basophils and mast cells for further activation causing allergic inflammation. E-NPP3 decreases ATP concentration and suppresses basophil and mast cell activity.


Asunto(s)
Adenosina Trifosfato/metabolismo , Asma/inmunología , Basófilos/inmunología , Mastocitos/inmunología , Hidrolasas Diéster Fosfóricas/inmunología , Pirofosfatasas/inmunología , Receptores de IgE/inmunología , Adenosina Trifosfato/farmacología , Animales , Basófilos/citología , Dermatitis por Contacto/inmunología , Diarrea/inmunología , Diarrea/patología , Inmunoglobulina E/inmunología , Mastocitos/citología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Anafilaxis Cutánea Pasiva/inmunología , Hidrolasas Diéster Fosfóricas/genética , Pirofosfatasas/genética , Interferencia de ARN , ARN Interferente Pequeño , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/inmunología , Trinitrobencenos/inmunología
11.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-34548395

RESUMEN

Extracellular adenosine triphosphate (ATP) released by mucosal immune cells and by microbiota in the intestinal lumen elicits diverse immune responses that mediate the intestinal homeostasis via P2 purinergic receptors, while overactivation of ATP signaling leads to mucosal immune system disruption, which leads to pathogenesis of intestinal inflammation. In the small intestine, hydrolysis of luminal ATP by ectonucleoside triphosphate diphosphohydrolase (E-NTPD)7 in epithelial cells is essential for control of the number of T helper 17 (Th17) cells. However, the molecular mechanism by which microbiota-derived ATP in the colon is regulated remains poorly understood. Here, we show that E-NTPD8 is highly expressed in large-intestinal epithelial cells and hydrolyzes microbiota-derived luminal ATP. Compared with wild-type mice, Entpd8-/- mice develop more severe dextran sodium sulfate-induced colitis, which can be ameliorated by either the depletion of neutrophils and monocytes by injecting with anti-Gr-1 antibody or the introduction of P2rx4 deficiency into hematopoietic cells. An increased level of luminal ATP in the colon of Entpd8-/- mice promotes glycolysis in neutrophils through P2x4 receptor-dependent Ca2+ influx, which is linked to prolonged survival and elevated reactive oxygen species production in these cells. Thus, E-NTPD8 limits intestinal inflammation by controlling metabolic alteration toward glycolysis via the P2X4 receptor in myeloid cells.


Asunto(s)
Adenosina Trifosfatasas/fisiología , Adenosina Trifosfato/metabolismo , Colitis/prevención & control , Glucólisis , Células Mieloides/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Células Th17/inmunología , Animales , Células Cultivadas , Colitis/etiología , Colitis/metabolismo , Colitis/patología , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/inmunología , Células Mieloides/patología , Receptores Purinérgicos P2X4/genética , Transducción de Señal
12.
Biochem Biophys Res Commun ; 669: 103-112, 2023 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-37269592

RESUMEN

Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a pivotal role in the induction of inflammatory responses not only in innate immune cells but also in non-immune cells, leading to the activation of adaptive immunity. Signal transduction mediated by TRAF6, along with its upstream molecule MyD88 in intestinal epithelial cells (IECs) is crucial for the maintenance of mucosal homeostasis following inflammatory insult. The IEC-specific TRAF6-deficient (TRAF6ΔIEC) and MyD88-deficient (MyD88ΔIEC) mice exhibit increased susceptibility to DSS-induced colitis, emphasizing the critical role of this pathway. Moreover, MyD88 also plays a protective role in Citrobacter rodentium (C. rodentium) infection-induced colitis. However, its pathological role of TRAF6 in infectious colitis remains unclear. To investigate the site-specific roles of TRAF6 in response to enteric bacterial pathogens, we infected TRAF6ΔIEC and dendritic cell (DC)-specific TRAF6-deficient (TRAF6ΔDC) mice with C. rodentium and found that the pathology of infectious colitis was exacerbated with significantly decreased survival rates in TRAF6ΔDC mice, but not in TRAF6ΔIEC mice, compared to those in control mice. TRAF6ΔDC mice showed increased bacterial burdens, marked disruption of epithelial and mucosal structures with increased infiltration of neutrophils and macrophages, and elevated cytokine levels in the colon at the late stages of infection. The frequencies of IFN-γ producing Th1 cells and IL-17A producing Th17 cells in the colonic lamina propria were significantly reduced in TRAF6ΔDC mice. Finally, we demonstrated that TRAF6-deficient DCs failed to produce IL-12 and IL-23 in response to C. rodentium stimulation, and to induce both Th1 and Th17 cells in vitro. Thus, TRAF6 signaling in DCs, but not in IECs, protects against colitis induced by C. rodentium infection by producing IL-12 and IL-23 that induce Th1 and Th17 responses in the gut.


Asunto(s)
Citrobacter rodentium , Colitis , Animales , Ratones , Citrobacter rodentium/metabolismo , Factor 6 Asociado a Receptor de TNF/genética , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Células Th17 , Colitis/patología , Transducción de Señal , Mucosa Intestinal/metabolismo , Colon/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células Dendríticas/metabolismo , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Ratones Endogámicos C57BL , Células TH1/metabolismo
13.
Cancer Immunol Immunother ; 72(1): 39-53, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35699757

RESUMEN

Wilms' tumor 1 (WT1) is a promising tumor-associated antigen for cancer immunotherapy. We developed an oral protein vaccine platform composed of WT1-anchored, genetically engineered Bifidobacterium longum (B. longum) and conducted an in vivo study in mice to examine its anticancer activity. Mice were orally treated with phosphate-buffered saline, wild-type B. longum105-A, B. longum 2012 displaying only galacto-N-biose/lacto-N-biose I-binding protein (GLBP), and WT1 protein- and GLBP-expressing B. longum 420. Tumor size reduced significantly in the B. longum 420 group than in the B. longum 105-A and 2012 groups (P < 0.00 l each), indicating B. longum 420's antitumor activity via WT1-specific immune responses. CD8+ T cells played a major role in the antitumor activity of B. longum 420. The proportion of CD103+CD11b+CD11c+ dendritic cells (DCs) increased in the Peyer's patches (PPs) from mice in the B. longum 420 group, indicating the definite activation of DCs. In the PPs, the number and proportion of CD8+ T cells capable of producing interferon-gamma were significantly greater in the B. longum 420 group than in the B. longum 2012 group (P < 0.05 or < 0.01). The production of WT1-specific IgG antibody was significantly higher in the B. longum 420 group than in the 2012 group (P < 0.05). The B. longum 420 group showed the most intense intratumoral infiltration of CD4+ and CD8+ T cells primed by activated DCs in the PPs of mice in the B. longum 420 group. Our findings provide insights into a novel, intestinal bacterium-based, cancer immunotherapy through intestinal immunity.


Asunto(s)
Bifidobacterium longum , Vacunas contra el Cáncer , Leucemia Mieloide Aguda , Ratones , Animales , Proteínas WT1 , Linfocitos T CD8-positivos
14.
Genes Cells ; 27(4): 243-253, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35075728

RESUMEN

MicroRNAs are a class of non-coding short-chained RNAs that control cellular functions by downregulating their target genes. Recent research indicates that microRNAs play a role in the maintenance of gut homeostasis. miR-215 was found to be highly expressed in epithelial cells of the small intestine; however, the involvement of miR-215 in gut immunity remains unknown. Here, we show that miR-215 negatively regulates inflammation in the small intestine by inhibiting CXCL12 production. Mice lacking miR-215 showed high susceptibility to inflammation induced by indomethacin, accompanied by an increased number of Th17 cells in the lamina propria of the small intestine. Our findings provide a rationale for targeting miR-215 as a therapeutic intervention for inflammatory conditions in the small intestine.


Asunto(s)
Inflamación , Intestino Delgado , MicroARNs , Células Th17 , Animales , Inflamación/genética , Intestino Delgado/inmunología , Ratones , MicroARNs/genética
15.
Ann Rheum Dis ; 82(5): 621-629, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36627170

RESUMEN

OBJECTIVES: Prevotella copri is considered to be a contributing factor in rheumatoid arthritis (RA). However, in some non-Westernised countries, healthy individuals also harbour an abundance of P. copri in the intestine. This study investigated the pathogenicity of RA patient-derived P. copri (P. copri RA) compared with healthy control-derived P. copri (P. copri HC). METHODS: We obtained 13 P. copri strains from the faeces of patients with RA and healthy controls. Following whole genome sequencing, the sequences of P. copri RA and P. copri HC were compared. To analyse the arthritis-inducing ability of P. copri, we examined two arthritis models (1) a collagen-induced arthritis model harbouring P. copri under specific-pathogen-free conditions and (2) an SKG mouse arthritis model under P. copri-monocolonised conditions. Finally, to evaluate the ability of P. copri to activate innate immune cells, we performed in vitro stimulation of bone marrow-derived dendritic cells (BMDCs) by P. copri RA and P. copri HC. RESULTS: Comparative genomic analysis revealed no apparent differences in the core gene contents between P. copri RA and P. copri HC, but pangenome analysis revealed the high genome plasticity of P. copri. We identified a P. copri RA-specific genomic region as a conjugative transposon. In both arthritis models, P. copri RA-induced more severe arthritis than P. copri HC. In vitro BMDC stimulation experiments revealed the upregulation of IL-17 and Th17-related cytokines (IL-6, IL-23) by P. copri RA. CONCLUSION: Our findings reveal the genetic diversity of P. copri, and the genomic signatures associated with strong arthritis-inducing ability of P. copri RA. Our study contributes towards elucidation of the complex pathogenesis of RA.


Asunto(s)
Artritis Reumatoide , Microbioma Gastrointestinal , Animales , Ratones , Microbioma Gastrointestinal/genética , Artritis Reumatoide/genética , Prevotella/genética , Genómica , Modelos Animales de Enfermedad
16.
Int Immunol ; 34(7): 343-352, 2022 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-35303081

RESUMEN

CX3CR1high myeloid cells in the small intestine mediate the induction of oral tolerance by driving regulatory T (Treg) cells. Bacterial metabolites, e.g. pyruvate and lactate, induce a dendrite extension of CX3CR1high myeloid cells into the intestinal lumen via GPR31. However, it remains unclear whether the pyruvate-GPR31 axis is involved in the induction of oral tolerance. Here, we show that pyruvate enhances oral tolerance in a GPR31-dependent manner. In ovalbumin (OVA)-fed Gpr31-deficient mice, an OVA-induced delayed-type hypersensitivity response was substantially induced, demonstrating the defective induction of oral tolerance in Gpr31-deficient mice. The percentage of RORγt+ Treg cells in the small intestine was reduced in Gpr31-deficient mice. In pyruvate-treated wild-type mice, a low dose of OVA efficiently induced oral tolerance. IL-10 production from intestinal CX3CR1high myeloid cells was increased by OVA ingestion in wild-type mice, but not in Gpr31-deficient mice. CX3CR1high myeloid cell-specific IL-10-deficient mice showed a defective induction of oral tolerance to OVA and a decreased accumulation of OVA-specific Treg cells in the small intestine. These findings demonstrate that pyruvate enhances oral tolerance through a GPR31-dependent effect on intestinal CX3CR1high myeloid cells.


Asunto(s)
Hipersensibilidad Tardía , Tolerancia Inmunológica , Ácido Pirúvico , Receptores Acoplados a Proteínas G , Administración Oral , Animales , Receptor 1 de Quimiocinas CX3C , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/prevención & control , Interleucina-10 , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Ácido Pirúvico/metabolismo , Receptores Acoplados a Proteínas G/genética , Linfocitos T Reguladores/metabolismo
17.
Immunity ; 41(6): 1040-51, 2014 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-25484301

RESUMEN

B cells can suppress autoimmunity by secreting interleukin-10 (IL-10). Although subpopulations of splenic B lineage cells are reported to express IL-10 in vitro, the identity of IL-10-producing B cells with regulatory function in vivo remains unknown. By using IL-10 reporter mice, we found that plasmablasts in the draining lymph nodes (dLNs), but not splenic B lineage cells, predominantly expressed IL-10 during experimental autoimmune encephalomyelitis (EAE). These plasmablasts were generated only during EAE inflammation. Mice lacking plasmablasts by genetic ablation of the transcription factors Blimp1 or IRF4 in B lineage cells developed an exacerbated EAE. Furthermore, IRF4 positively regulated IL-10 production that can inhibit dendritic cell functions to generate pathogenic T cells. Our data demonstrate that plasmablasts in the dLNs serve as IL-10 producers to limit autoimmune inflammation and emphasize the importance of plasmablasts as IL-10-producing regulatory B cells.


Asunto(s)
Linfocitos B Reguladores/inmunología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Células Plasmáticas/fisiología , Linfocitos T/inmunología , Animales , Células Cultivadas , Humanos , Tolerancia Inmunológica , Inflamación/genética , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Bazo/inmunología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
18.
Int J Cancer ; 151(4): 623-636, 2022 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-35403732

RESUMEN

Western high-fat diets (HFD) are regarded as a major risk factor for prostate cancer (PCa). Using prostate-specific Pten-knockout mice as a PCa model, we previously reported that HFD promoted inflammatory PCa growth. The composition of the gut microbiota changes under the influence of diet exert various effects on the host through immunological mechanisms. Herein, we investigated the etiology of HFD-induced inflammatory cancer growth and the involvement of the gut microbiome. The expression of Hdc, the gene responsible for histamine biosynthesis, and histamine levels were upregulated in large prostate tumors of HFD-fed mice, and the number of mast cells increased around the tumor foci. Administration of fexofenadine, a histamine H1 receptor antagonist, suppressed tumor growth in HFD-fed mice by reducing the number of myeloid-derived suppressor cells and suppressing IL6/STAT3 signaling. HFD intake induced gut dysbiosis, resulting in the elevation of serum lipopolysaccharide (LPS) levels. Intraperitoneal injection of LPS increased Hdc expression in PCa. Inhibition of LPS/Toll-like receptor 4 signaling suppressed HFD-induced tumor growth. The number of mast cells increased around the cancer foci in total prostatectomy specimens of severely obese patients. In conclusion, HFD promotes PCa growth through histamine signaling via mast cells. Dietary high-fat induced gut dysbiosis might be involved in the inflammatory cancer growth.


Asunto(s)
Dieta Alta en Grasa , Neoplasias de la Próstata , Animales , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta , Disbiosis , Histamina , Humanos , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias de la Próstata/etiología
19.
Genes Cells ; 26(10): 807-822, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34379860

RESUMEN

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine, and the dysfunction of intestinal epithelial barrier (IEB) may trigger the onset of IBD. Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor that has been implicated in the tissue-protective effect in the skin and lung. We found that SLPI was induced in lipopolysaccharides-treated colon carcinoma cell line and in the colon of dextran sulfate sodium (DSS)-treated mice. SLPI-deficient mice were administered DSS to induce colitis and sustained severe inflammation compared with wild-type mice. The colonic mucosa of SLPI-deficient mice showed more severe inflammation with neutrophil infiltration and higher levels of proinflammatory cytokines compared with control mice. Moreover, neutrophil elastase (NE) activity in SLPI-deficient mice was increased and IEB function was severely impaired in the colon, accompanied with the increased number of apoptotic cells. Importantly, we demonstrated that DSS-induced colitis was ameliorated by administration of protease inhibitor SSR69071 and recombinant SLPI. These results suggest that the protease inhibitory activity of SLPI protects from colitis by preventing IEB dysfunction caused by excessive NE activity, which provides insight into the novel function of SLPI in the regulation of gut homeostasis and therapeutic approaches for IBD.


Asunto(s)
Colitis , Inhibidor Secretorio de Peptidasas Leucocitarias , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Mucosa Intestinal , Ratones , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Inhibidores de Serina Proteinasa
20.
Nature ; 532(7597): 117-21, 2016 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-27027293

RESUMEN

Colonic epithelial cells are covered by thick inner and outer mucus layers. The inner mucus layer is free of commensal microbiota, which contributes to the maintenance of gut homeostasis. In the small intestine, molecules critical for prevention of bacterial invasion into epithelia such as Paneth-cell-derived anti-microbial peptides and regenerating islet-derived 3 (RegIII) family proteins have been identified. Although there are mucus layers providing physical barriers against the large number of microbiota present in the large intestine, the mechanisms that separate bacteria and colonic epithelia are not fully elucidated. Here we show that Ly6/PLAUR domain containing 8 (Lypd8) protein prevents flagellated microbiota invading the colonic epithelia in mice. Lypd8, selectively expressed in epithelial cells at the uppermost layer of the large intestinal gland, was secreted into the lumen and bound flagellated bacteria including Proteus mirabilis. In the absence of Lypd8, bacteria were present in the inner mucus layer and many flagellated bacteria invaded epithelia. Lypd8(-/-) mice were highly sensitive to intestinal inflammation induced by dextran sulfate sodium (DSS). Antibiotic elimination of Gram-negative flagellated bacteria restored the bacterial-free state of the inner mucus layer and ameliorated DSS-induced intestinal inflammation in Lypd8(-/-) mice. Lypd8 bound to flagella and suppressed motility of flagellated bacteria. Thus, Lypd8 mediates segregation of intestinal bacteria and epithelial cells in the colon to preserve intestinal homeostasis.


Asunto(s)
Colon/microbiología , Epitelio/microbiología , Flagelos , Proteínas Ligadas a GPI/metabolismo , Bacterias Gramnegativas/fisiología , Mucosa Intestinal/microbiología , Animales , Adhesión Bacteriana , Células CACO-2 , Línea Celular , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/genética , Sulfato de Dextran , Femenino , Proteínas Ligadas a GPI/deficiencia , Proteínas Ligadas a GPI/genética , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/metabolismo , Bacterias Gramnegativas/patogenicidad , Homeostasis , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/genética , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Masculino , Ratones , Proteus mirabilis/efectos de los fármacos , Proteus mirabilis/metabolismo , Proteus mirabilis/patogenicidad , Simbiosis
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