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1.
Nature ; 615(7950): 151-157, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36509106

RESUMEN

In the past decade, single-cell transcriptomics has helped to uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils-elusive granulocytes that are implicated in a plethora of human pathologies1-5-are among these uncharted cell types. The heterogeneity of eosinophils and the gene programs that underpin their pleiotropic functions remain poorly understood. Here we provide a comprehensive single-cell transcriptomic profiling of mouse eosinophils. We identify an active and a basal population of intestinal eosinophils, which differ in their transcriptome, surface proteome and spatial localization. By means of a genome-wide CRISPR inhibition screen and functional assays, we reveal a mechanism by which interleukin-33 (IL-33) and interferon-γ (IFNγ) induce the accumulation of active eosinophils in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of patients with inflammatory bowel disease, and are closely associated with CD4+ T cells. Our findings provide insights into the biology of eosinophils and highlight the crucial contribution of this cell type to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.


Asunto(s)
Colitis , Eosinófilos , Inmunidad , Intestinos , Animales , Humanos , Ratones , Colitis/inmunología , Colitis/patología , Eosinófilos/clasificación , Eosinófilos/citología , Eosinófilos/inmunología , Eosinófilos/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Análisis de Expresión Génica de una Sola Célula , Transcriptoma , Proteoma , Interleucina-33 , Interferón gamma , Linfocitos T , Antígeno B7-1/metabolismo , Intestinos/inmunología , Intestinos/patología
2.
Immunity ; 43(1): 187-99, 2015 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-26200014

RESUMEN

The role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target.


Asunto(s)
Colitis/inmunología , Eosinófilos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Animales , Movimiento Celular/inmunología , Subunidad beta Común de los Receptores de Citocinas/genética , Peroxidasa del Eosinófilo/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Inflamación/inmunología , Interleucina-5/antagonistas & inhibidores , Intestinos/citología , Intestinos/inmunología , Intestinos/patología , Procedimientos de Reducción del Leucocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Factores de Necrosis Tumoral/metabolismo
3.
Blood ; 137(21): 2958-2969, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-33598715

RESUMEN

Eosinophils are white blood cells that contribute to the regulation of immunity and are involved in the pathogenesis of numerous inflammatory diseases. In contrast to other cells of the immune system, no information is available regarding the role of autophagy in eosinophil differentiation and functions. To study the autophagic pathway in eosinophils, we generated conditional knockout mice in which Atg5 is deleted within the eosinophil lineage only (designated Atg5eoΔ mice). Eosinophilia was provoked by crossbreeding Atg5eoΔ mice with Il5 (IL-5) overexpressing transgenic mice (designated Atg5eoΔIl5tg mice). Deletion of Atg5 in eosinophils resulted in a dramatic reduction in the number of mature eosinophils in blood and an increase of immature eosinophils in the bone marrow. Atg5-knockout eosinophil precursors exhibited reduced proliferation under both in vitro and in vivo conditions but no increased cell death. Moreover, reduced differentiation of eosinophils in the absence of Atg5 was also observed in mouse and human models of chronic eosinophilic leukemia. Atg5-knockout blood eosinophils exhibited augmented levels of degranulation and bacterial killing in vitro. Moreover, in an experimental in vivo model, we observed that Atg5eoΔ mice achieve better clearance of the local and systemic bacterial infection with Citrobacter rodentium. Evidence for increased degranulation of ATG5low-expressing human eosinophils was also obtained in both tissues and blood. Taken together, mouse and human eosinophil hematopoiesis and effector functions are regulated by ATG5, which controls the amplitude of overall antibacterial eosinophil immune responses.


Asunto(s)
Proteína 5 Relacionada con la Autofagia/fisiología , Eosinófilos/fisiología , Mielopoyesis/fisiología , Animales , Proteína 5 Relacionada con la Autofagia/biosíntesis , Proteína 5 Relacionada con la Autofagia/deficiencia , Proteína 5 Relacionada con la Autofagia/genética , Médula Ósea/patología , Sistemas CRISPR-Cas , Degranulación de la Célula , Línea Celular Tumoral , Células Cultivadas , Citrobacter rodentium , Ensayo de Unidades Formadoras de Colonias , Infecciones por Enterobacteriaceae/inmunología , Eosinófilos/citología , Eosinófilos/inmunología , Humanos , Síndrome Hipereosinofílico/sangre , Síndrome Hipereosinofílico/patología , Interleucina-5/genética , Recuento de Leucocitos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas de Fusión Oncogénica/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Factores de Escisión y Poliadenilación de ARNm/genética
4.
J Immunol ; 205(7): 1933-1943, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32848032

RESUMEN

The lamina propria of the gastrointestinal tract and other mucosal surfaces of humans and mice host a network of mononuclear phagocytes that differ in their ontogeny, surface marker and transcription factor expression, and functional specialization. Conventional dendritic cells (DCs) in particular exist as two major subpopulations in both lymphoid and nonlymphoid organs that can be distinguished based on their surface marker and transcription factor expression. In this study, we show in various Th1- and/or Th17-polarized settings of acute and chronic bacterial infection and of tumor growth that the conditional ablation of Irf4 in CD11c+ DCs results in more efficient immune control of Helicobacter pylori, Mycobacterium bovis bacillus Calmette-Guérin, and Citrobacter rodentium and of tumor growth in a syngeneic tumor model. We attribute the phenotype of IRF4ΔDC mice to unrestricted Th1 responses and in particular to IFN-γ- and TNF-α-expressing CD4+ T cells. This activity of IRF4-expressing DCs is linked to a DC-specific immunoregulatory transcriptional program. In contrast, in Th2-polarized settings such as house dust mite-induced allergic airway inflammation, the lack of IRF4 expression in the DC compartment alleviates inflammation and goblet cell metaplasia. The combined data provide evidence for immunoregulatory properties of this versatile DC population in Th1-polarized infection settings.


Asunto(s)
Células Dendríticas/inmunología , Infecciones por Helicobacter/inmunología , Helicobacter pylori/fisiología , Factores Reguladores del Interferón/metabolismo , Neoplasias Experimentales/inmunología , Hipersensibilidad Respiratoria/inmunología , Neoplasias Gástricas/inmunología , Células TH1/inmunología , Células Th2/inmunología , Animales , Antígenos Dermatofagoides/inmunología , Antígeno CD11c/metabolismo , Proliferación Celular , Células Cultivadas , Enfermedad Crónica , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Inmunomodulación , Factores Reguladores del Interferón/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pyroglyphidae
5.
PLoS Pathog ; 15(6): e1007866, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31188899

RESUMEN

The gastric lamina propria of mice that have been experimentally infected with the pathobiont Helicobacter pylori hosts a dense network of myeloid cells that includes BATF3-dependent CD103+ dendritic cells (DCs). We show here that CD103+ DCs are strictly required for gastric Th1 responses to H. pylori and for H. pylori infection control. A similar dependence of type 1 immunity on CD103+ DCs is observed in a Mycobacterium bovis BCG infection model, and in a syngeneic colon cancer model. Strikingly, we find that not only the expansion and/or recruitment of Th1 cells, but also of peripherally induced, neuropilin-negative regulatory T-cells to sites of infection requires BATF3-dependent DCs. A shared feature of the examined models is the strongly reduced production of the chemokines and CXCR3 ligands CXCL9, 10 and 11 in BATF3-deficient mice. The results implicate BATF3-dependent DCs in the recruitment of CXCR3+ effector and regulatory T-cells to target tissues and in their local expansion.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Células Dendríticas/inmunología , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Mycobacterium bovis/inmunología , Proteínas Represoras/inmunología , Linfocitos T Reguladores/inmunología , Tuberculosis/inmunología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Línea Celular Tumoral , Quimiocinas CXC/genética , Quimiocinas CXC/inmunología , Células Dendríticas/microbiología , Células Dendríticas/patología , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/patología , Ratones , Ratones Noqueados , Receptores CXCR3/genética , Receptores CXCR3/inmunología , Proteínas Represoras/genética , Linfocitos T Reguladores/microbiología , Linfocitos T Reguladores/patología , Tuberculosis/genética , Tuberculosis/patología
6.
Int Arch Allergy Immunol ; 181(1): 11-23, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31786573

RESUMEN

Eosinophils and their secretory mediators play an important role in the pathogenesis of infectious and inflammatory disorders. Although eosinophils are largely evolutionally conserved, their physiologic functions are not well understood. Given the availability of new eosinophil-targeted depletion therapies, there has been a renewed interest in understanding eosinophil biology as these strategies may result in secondary disorders when applied over long periods of time. Recent data suggest that eosinophils are not only involved in immunological effector functions but also carry out tissue protective and immunoregulatory functions that actively contribute to the maintenance of homeostasis. Prolonged eosinophil depletion may therefore result in the development of secondary disorders. Here, we review recent literature pointing to important roles for eosinophils in promoting immune defense, antibody production, activation of adipose tissue, and tissue remodeling and fibrosis. We also reflect on patient data from clinical trials that feature anti-eosinophil therapeutics.


Asunto(s)
Eosinófilos/inmunología , Síndrome Hipereosinofílico/inmunología , Inflamación/inmunología , Animales , Formación de Anticuerpos , Humanos , Inmunidad Celular , Inmunomodulación , Interleucina-5 , Cicatrización de Heridas
7.
Nat Protoc ; 19(6): 1679-1709, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38504138

RESUMEN

Eosinophils are a class of granulocytes with pleiotropic functions in homeostasis and various human diseases. Nevertheless, they are absent from conventional single-cell RNA sequencing atlases owing to technical difficulties preventing their transcriptomic interrogation. Consequently, eosinophil heterogeneity and the gene regulatory networks underpinning their diverse functions remain poorly understood. We have developed a stress-free protocol for single-cell RNA capture from murine tissue-resident eosinophils, which revealed distinct intestinal subsets and their roles in colitis. Here we describe in detail how to enrich eosinophils from multiple tissues of residence and how to capture high-quality single-cell transcriptomes by preventing transcript degradation. By combining magnetic eosinophil enrichment with microwell-based single-cell RNA capture (BD Rhapsody), our approach minimizes shear stress and processing time. Moreover, we report how to perform genome-wide CRISPR pooled genetic screening in ex vivo-conditioned bone marrow-derived eosinophils to functionally probe pathways required for their differentiation and intestinal maturation. These protocols can be performed by any researcher with basic skills in molecular biology and flow cytometry, and can be adapted to investigate other granulocytes, such as neutrophils and mast cells, thereby offering potential insights into their roles in both homeostasis and disease pathogenesis. Single-cell transcriptomics of eosinophils can be performed in 2-3 d, while functional genomics assays may require up to 1 month.


Asunto(s)
Eosinófilos , Perfilación de la Expresión Génica , Análisis de la Célula Individual , Animales , Análisis de la Célula Individual/métodos , Eosinófilos/metabolismo , Ratones , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Transcriptoma/genética , Ratones Endogámicos C57BL
8.
J Immunol ; 186(11): 6165-72, 2011 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-21518972

RESUMEN

Chronic infection with the human bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to an increased gastric cancer risk. Consequently, H. pylori-specific vaccination is widely viewed as a promising strategy of gastric cancer prevention. H. pylori strains harboring the Cag pathogenicity island (PAI) are associated with particularly unfavorable disease outcomes in humans and experimental rodent models. We show in this study using a C57BL/6 mouse model of Cag-PAI(+) H. pylori infection that the only known protein substrate of the Cag-PAI-encoded type IV secretion system, the cytotoxin-associated gene A (CagA) protein, harbors MHC class II-restricted T cell epitopes. Several distinct nonoverlapping epitopes in CagA's central and C-terminal regions were predicted in silico and could be confirmed experimentally. CagA(+) infection elicits CD4(+) T cell responses in mice, which are strongly enhanced by prior mucosal or parenteral vaccination with recombinant CagA. The adoptive transfer of CagA-specific T cells to T cell-deficient, H. pylori-infected recipients is sufficient to induce the full range of preneoplastic immunopathology. Similarly, immunization with a cholera toxin-adjuvanted, CagA(+) whole-cell sonicate vaccine sensitizes mice to, rather than protects them from, H. pylori-associated gastric cancer precursor lesions. In contrast, H. pylori-specific tolerization by neonatal administration of H. pylori sonicate in conjunction with a CD40L-neutralizing Ab prevents H. pylori-specific, pathogenic T cell responses and gastric immunopathology. We conclude that active tolerization may be superior to vaccination strategies in gastric cancer prevention.


Asunto(s)
Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Epítopos de Linfocito T/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Neoplasias Gástricas/inmunología , Traslado Adoptivo , Animales , Animales Recién Nacidos , Antígenos Bacterianos/química , Antígenos Bacterianos/genética , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Vacunas Bacterianas/inmunología , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/prevención & control , Helicobacter pylori/inmunología , Helicobacter pylori/patogenicidad , Helicobacter pylori/fisiología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunización/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/prevención & control , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/trasplante , Células TH1/inmunología , Células TH1/metabolismo , Virulencia
9.
J Exp Med ; 220(7)2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-37326974

RESUMEN

Eosinophils are typically considered tissue-damaging effector cells in type 2 immune-related diseases. However, they are also increasingly recognized as important modulators of various homeostatic processes, suggesting they retain the ability to adapt their function to different tissue contexts. In this review, we discuss recent progress in our understanding of eosinophil activities within tissues, with particular emphasis on the gastrointestinal tract, where a large population of these cells resides under non-inflammatory conditions. We further examine evidence of their transcriptional and functional heterogeneity and highlight environmental signals emerging as key regulators of their activities, beyond classical type 2 cytokines.


Asunto(s)
Eosinófilos , Enfermedades del Sistema Inmune , Humanos , Citocinas , Tracto Gastrointestinal
10.
Gastroenterology ; 140(1): 199-209, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20600031

RESUMEN

BACKGROUND & AIMS: Chronic infection with the bacterial pathogen Helicobacter pylori causes gastric disorders, ranging from chronic gastritis to gastric adenocarcinoma. Only a subset of infected persons will develop overt disease; most remains asymptomatic despite lifelong colonization. This study aims to elucidate the differential susceptibility to H pylori that is found both across and within populations. METHODS: We have established a C57BL/6 mouse model of H pylori infection with a strain that is capable of delivering the virulence factor cytotoxin-associated gene A (CagA) into host cells through the activity of a Cag-pathogenicity island-encoded type IV secretion system. RESULTS: Mice infected at 5-6 weeks of age with CagA(+)H pylori rapidly develop gastritis, gastric atrophy, epithelial hyperplasia, and metaplasia in a type IV secretion system-dependent manner. In contrast, mice infected during the neonatal period with the same strain are protected from preneoplastic lesions. Their protection results from the development of H pylori-specific peripheral immunologic tolerance, which requires transforming growth factor-ß signaling and is mediated by long-lived, inducible regulatory T cells, and which controls the local CD4(+) T-cell responses that trigger premalignant transformation. Tolerance to H pylori develops in the neonatal period because of a biased ratio of T-regulatory to T-effector cells and is favored by prolonged low-dose exposure to antigen. CONCLUSIONS: Using a novel CagA(+)H pylori infection model, we report here that the development of tolerance to H pylori protects from gastric cancer precursor lesions. The age at initial infection may thus account for the differential susceptibility of infected persons to H pylori-associated disease manifestations.


Asunto(s)
Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Tolerancia Inmunológica , Lesiones Precancerosas/microbiología , Gastropatías/microbiología , Animales , Sistemas de Secreción Bacterianos/inmunología , Femenino , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Islas Genómicas/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Hiperplasia/inmunología , Hiperplasia/microbiología , Masculino , Metaplasia/inmunología , Metaplasia/microbiología , Ratones , Ratones Endogámicos C57BL , Lesiones Precancerosas/inmunología , Gastropatías/inmunología , Gastropatías/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/microbiología
11.
Cell Commun Signal ; 9(1): 25, 2011 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-22044597

RESUMEN

Persistent infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high gastric cancer risk, but has also been linked to protection from allergic, chronic inflammatory and autoimmune diseases. In the course of tens of thousands of years of co-existence with its human host, H. pylori has evolved elaborate adaptations that allow it to persist in the hostile environment of the stomach in the face of a vigorous innate and adaptive immune response. For this review, we have identified several key immune cell types and signaling pathways that appear to be preferentially targeted by the bacteria to establish and maintain persistent infection. We explore the mechanisms that allow the bacteria to avoid detection by innate immune cells via their pattern recognition receptors, to escape T-cell mediated adaptive immunity, and to reprogram the immune system towards tolerance rather than immunity. The implications of the immunomodulatory properties of the bacteria for the prevention of allergic and auto-immune diseases in chronically infected individuals are also discussed.

12.
Semin Immunopathol ; 43(3): 295-306, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33929602

RESUMEN

Eosinophils are traditionally considered as end-stage effector cells involved in the pathogenesis of Th2 immune-mediated disorders as well as in the protection against parasite infection. However, this restricted view has recently been challenged by a series of studies revealing the highly plastic nature of these cells and implication in various homeostatic processes. Large numbers of eosinophils reside in the lamina propria of the gastrointestinal tract, at the front line of host defence, where they contribute to maintain the intestinal epithelial barrier function in the face of inflammation-associated epithelial cell damage. Eosinophils confer active protection against bacterial pathogens capable of penetrating the mucosal barrier through the release of cytotoxic compounds and the generation of extracellular DNA traps. Eosinophils also integrate tissue-specific cytokine signals such as IFN-γ, which synergise with bacterial recognition pathways to enforce different context-dependent functional responses, thereby ensuring a rapid adaptation to the ever-changing intestinal environment. The ability of eosinophils to regulate local immune responses and respond to microbial stimuli further supports the pivotal role of these cells in the maintenance of tissue homeostasis at the intestinal interface.


Asunto(s)
Eosinófilos , Intestinos , Citocinas , Homeostasis , Humanos , Inflamación , Mucosa Intestinal
13.
Nat Commun ; 12(1): 1368, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33649334

RESUMEN

The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/ß-catenin signaling is required for IESC maintenance, however, it remains unclear how this pathway selectively governs the identity and proliferative decisions of IESCs. Here, we took advantage of knock-in mice harboring transgenic ß-catenin alleles with mutations that specifically impair the recruitment of N- or C-terminal transcriptional co-factors. We show that C-terminally-recruited transcriptional co-factors of ß-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with ß-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune ß-catenin's transcriptional output to ensure proper self-renewal and proliferative behaviour of IESCs. Impairment of N-terminal interactions triggers transient hyperproliferation of IESCs, eventually resulting in exhaustion of the self-renewing stem cell pool. IESC mis-differentiation, accompanied by unfolded protein response stress and immune infiltration, results in a process resembling aberrant "villisation" of intestinal crypts. Our data suggest that IESC-specific Wnt/ß-catenin output requires selective modulation of gene expression by transcriptional co-factors.


Asunto(s)
Mucosa Intestinal/citología , Células Madre/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , beta Catenina/química , beta Catenina/metabolismo , Algoritmos , Animales , Secuencia de Bases , Diferenciación Celular , Proliferación Celular , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Homeostasis , Hiperplasia , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Proteínas Mutantes/metabolismo , Mutación/genética , Organoides/metabolismo , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal
14.
Cell Host Microbe ; 29(10): 1573-1588.e7, 2021 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-34453895

RESUMEN

Despite overall success, T cell checkpoint inhibitors for cancer treatment are still only efficient in a minority of patients. Recently, intestinal microbiota was found to critically modulate anti-cancer immunity and therapy response. Here, we identify Clostridiales members of the gut microbiota associated with a lower tumor burden in mouse models of colorectal cancer (CRC). Interestingly, these commensal species are also significantly reduced in CRC patients compared with healthy controls. Oral application of a mix of four Clostridiales strains (CC4) in mice prevented and even successfully treated CRC as stand-alone therapy. This effect depended on intratumoral infiltration and activation of CD8+ T cells. Single application of Roseburia intestinalis or Anaerostipes caccae was even more effective than CC4. In a direct comparison, the CC4 mix supplementation outperformed anti-PD-1 therapy in mouse models of CRC and melanoma. Our findings provide a strong preclinical foundation for exploring gut bacteria as novel stand-alone therapy against solid tumors.


Asunto(s)
Terapia Biológica , Clostridiales/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Microbioma Gastrointestinal , Animales , Linfocitos T CD8-positivos/inmunología , Clostridiales/fisiología , Neoplasias Colorrectales/microbiología , Humanos , Inmunidad , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Simbiosis
15.
Curr Opin Microbiol ; 54: 1-10, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32007716

RESUMEN

The gastric bacterium Helicobacter pylori efficiently evades innate immune detection and persistently colonizes its human host. Understanding the genetic determinants that H. pylori uses to establish and maintain persistence, along with their cellular targets, is key to our understanding of the pathogenesis of this extraordinarily successful bacterial colonizer of the human stomach. This review highlights recent advances in elucidating innate immune recognition of H. pylori, its interactions with myeloid cells and the consequences that this very local infection has for immune responses at extragastric sites in models of allergy, autoimmunity and parasitic infection. The human-specific, gram-negative gastric colonizer and carcinogen H. pylori represents the prototype of a persistent bacterial pathogen. It is transmitted during early childhood, typically from mother to infant, and is believed to persist in its human host from the cradle to the grave. The tremendous success of H. pylori in infecting and colonizing half of the world's population, and in continuously accompanying humans since they migrated out of Africa over 60000 years ago, can largely be attributed to its ability to manipulate the host immune system to its own advantage, and to thereby ensure its own persistence and chronicity. In his final years as an active PI, Stanley Falkow increasingly recognized the need to understand bacterial persistence strategies as a prerequisite of understanding the pathogenesis of chronic bacterial infections, and, inspired in large part by Denise Monack's work on Salmonella persistence, many of our discussions at the time revolved around this topic. Multiple labs have since made important contributions to our understanding of innate immune detection of H. pylori, the types and polarization of adaptive immune responses that ensue, the ability of H. pylori to skew such immune responses to its advantage, and its ability to manipulate the host immune system with far-reaching, even systemic consequences. This review attempts to cover some of these topics, with a particular focus on the most recent contributions by researchers in the field.


Asunto(s)
Mucosa Gástrica/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/inmunología , Helicobacter pylori/patogenicidad , Inmunidad Innata , Inmunomodulación , Animales , Autoinmunidad , Eosinófilos/inmunología , Eosinófilos/fisiología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/inmunología , Helicobacter pylori/fisiología , Interacciones Huésped-Patógeno , Humanos , Evasión Inmune , Factores Inmunológicos/metabolismo , Células Mieloides/inmunología , Células Mieloides/fisiología , Enfermedades Parasitarias/complicaciones , Enfermedades Parasitarias/inmunología , Virulencia
16.
J Exp Med ; 217(12)2020 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-32970801

RESUMEN

The depletion of eosinophils represents an efficient strategy to alleviate allergic asthma, but the consequences of prolonged eosinophil deficiency for human health remain poorly understood. We show here that the ablation of eosinophils severely compromises antitumor immunity in syngeneic and genetic models of colorectal cancer (CRC), which can be attributed to defective Th1 and CD8+ T cell responses. The specific loss of GM-CSF signaling or IRF5 expression in the eosinophil compartment phenocopies the loss of the entire lineage. GM-CSF activates IRF5 in vitro and in vivo and can be administered recombinantly to improve tumor immunity. IL-10 counterregulates IRF5 activation by GM-CSF. CRC patients whose tumors are infiltrated by large numbers of eosinophils also exhibit robust CD8 T cell infiltrates and have a better prognosis than patients with eosinophillow tumors. The combined results demonstrate a critical role of eosinophils in tumor control in CRC and introduce the GM-CSF-IRF5 axis as a critical driver of the antitumor activities of this versatile cell type.


Asunto(s)
Eosinófilos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Inmunidad , Factores Reguladores del Interferón/metabolismo , Neoplasias/inmunología , Transducción de Señal , Células TH1/inmunología , Adenoma/tratamiento farmacológico , Adenoma/inmunología , Adenoma/patología , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Eosinófilos/efectos de los fármacos , Eosinófilos/patología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunidad/efectos de los fármacos , Interleucina-10/metabolismo , Interleucina-5/metabolismo , Intestinos/patología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Ratones Endogámicos C57BL , Neoplasias/metabolismo , Neoplasias/patología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Células TH1/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Transgenes , Microambiente Tumoral/efectos de los fármacos
17.
Sci Immunol ; 5(47)2020 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-32444476

RESUMEN

Mononuclear phagocytes (MNPs) are vital for maintaining intestinal homeostasis but, in response to acute microbial stimulation, can also trigger immunopathology, accelerating recruitment of Ly6Chi monocytes to the gut. The regulators that control monocyte tissue adaptation in the gut remain poorly understood. Interferon regulatory factor 5 (IRF5) is a transcription factor previously shown to play a key role in maintaining the inflammatory phenotype of macrophages. Here, we investigate the impact of IRF5 on the MNP system and physiology of the gut at homeostasis and during inflammation. We demonstrate that IRF5 deficiency has a limited impact on colon physiology at steady state but ameliorates immunopathology during Helicobacter hepaticus-induced colitis. Inhibition of IRF5 activity in MNPs phenocopies global IRF5 deficiency. Using a combination of bone marrow chimera and single-cell RNA-sequencing approaches, we examined the intrinsic role of IRF5 in controlling colonic MNP development. We demonstrate that IRF5 promotes differentiation of Ly6Chi monocytes into CD11c+ macrophages and controls the production of antimicrobial and inflammatory mediators by these cells. Thus, we identify IRF5 as a key transcriptional regulator of the colonic MNP system during intestinal inflammation.


Asunto(s)
Antígenos CD11/inmunología , Inflamación/inmunología , Factores Reguladores del Interferón/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Animales , Helicobacter hepaticus/inmunología , Inflamación/patología , Factores Reguladores del Interferón/deficiencia , Macrófagos/patología , Ratones , Ratones Noqueados , Monocitos/patología , Fenotipo
18.
J Exp Med ; 215(8): 2055-2072, 2018 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-29970473

RESUMEN

Eosinophils are predominantly known for their contribution to allergy. Here, we have examined the function and regulation of gastrointestinal eosinophils in the steady-state and during infection with Helicobacter pylori or Citrobacter rodentium We find that eosinophils are recruited to sites of infection, directly encounter live bacteria, and activate a signature transcriptional program; this applies also to human gastrointestinal eosinophils in humanized mice. The genetic or anti-IL-5-mediated depletion of eosinophils results in improved control of the infection, increased inflammation, and more pronounced Th1 responses. Eosinophils control Th1 responses via the IFN-γ-dependent up-regulation of PD-L1. Furthermore, we find that the conditional loss of IFN-γR in eosinophils phenocopies the effects of eosinophil depletion. Eosinophils further possess bactericidal properties that require their degranulation and the deployment of extracellular traps. Our results highlight two novel functions of this elusive cell type and link it to gastrointestinal homeostasis and anti-bacterial defense.


Asunto(s)
Citrobacter rodentium/fisiología , Eosinófilos/inmunología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/patología , Helicobacter pylori/fisiología , Inflamación/inmunología , Inflamación/microbiología , Células TH1/inmunología , Enfermedad Aguda , Animales , Anticuerpos Antibacterianos/inmunología , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/patología , Degranulación de la Célula , Proliferación Celular , Colitis/inmunología , Colitis/microbiología , Colitis/patología , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Eosinófilos/fisiología , Trampas Extracelulares/metabolismo , Tracto Gastrointestinal/inmunología , Homeostasis , Inmunidad Innata , Inmunidad Mucosa , Inflamación/patología , Interferón gamma/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Células Th17/inmunología
19.
J Exp Med ; 215(8): 1987-1998, 2018 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-29980582

RESUMEN

Psoriasis is a complex inflammatory skin disease affecting ∼3% of the population worldwide. Although type I interferons (IFN-I) are thought to be involved in its pathogenesis, the details of this relationship remain elusive. Here we show that in a murine model of imiquimod-driven psoriatic skin inflammation, Foxp3+ regulatory T cells (T reg cells) control inflammation severity by restraining IFN-I. Depletion of T reg cells induces IFN-I and IFN-stimulated gene expression, and leads to accumulation of CD8+ T cells in lesional skin. Mononuclear phagocytes (MNPs) were the source of IFN-I, and their depletion reversed the effect of T reg cell depletion. Blockade of IFN-I signaling abolished CD8+ T cell infiltration and excess inflammation in the skin of T reg cell-depleted mice. Depletion of CD8+ T cells attenuated pathology, confirming their role as critical effector cells downstream of IFN-I. Our results describe an unexpected role for T reg cells in restraint of an MNP-IFN-I-driven CD8+ T cell response during psoriasiform skin inflammation. These findings highlight a pathway with potential relevance for the treatment of early-stage disease.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Factores de Transcripción Forkhead/metabolismo , Inflamación/inmunología , Interferón Tipo I/metabolismo , Psoriasis/inmunología , Linfocitos T Reguladores/inmunología , Animales , Ratones Endogámicos C57BL , Fagocitos/metabolismo , Índice de Severidad de la Enfermedad , Piel/patología
20.
Cell Rep ; 21(13): 3860-3872, 2017 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-29281833

RESUMEN

The gastric lamina propria is largely uncharted immunological territory. Here we describe the evolution and composition of the gastric, small intestinal, and colonic lamina propria mononuclear phagocyte system during the steady state and infection with the gastric pathogen Helicobacter pylori. We show that monocytes, CX3CR1hi macrophages, and CD11b+ dendritic cells are recruited to the infected stomach in a CCR2-dependent manner. All three populations, but not BATF3-dependent CD103+ DCs, sample red fluorescent protein (RFP)+Helicobacter pylori (H. pylori). Mice reconstituted with human hematopoietic stem cells recapitulate several features of the myeloid cell-H. pylori interaction. The differentiation in and/or recruitment to gastrointestinal, lung, and lymphoid tissues of CD11b+ DCs requires NLRP3, but not apoptosis-associated speck-like protein containing a carboxy-terminal CARD (ASC) or caspase-1, during steady-state and chronic infection. NLRP3-/- mice fail to generate Treg responses to H. pylori and control the infection more effectively than wild-type mice. The results demonstrate a non-canonical inflammasome-independent function of NLRP3 in DC development and immune regulation.


Asunto(s)
Antígeno CD11b/metabolismo , Células Dendríticas/inmunología , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/patología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Diferenciación Celular , Enfermedad Crónica , Femenino , Mucosa Gástrica/patología , Infecciones por Helicobacter/patología , Helicobacter pylori/fisiología , Humanos , Sistema Inmunológico/metabolismo , Inflamasomas/metabolismo , Pulmón/patología , Tejido Linfoide/patología , Macrófagos/metabolismo , Masculino , Ratones , Membrana Mucosa/metabolismo , Membrana Mucosa/patología , Células Mieloides/metabolismo , Fagocitos/metabolismo , Fagocitosis , Receptores CCR2/metabolismo , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Receptor Toll-Like 2/metabolismo , Regulación hacia Arriba
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