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1.
Annu Rev Immunol ; 33: 643-75, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25861979

RESUMEN

Macrophages are myeloid immune cells that are strategically positioned throughout the body tissues, where they ingest and degrade dead cells, debris, and foreign material and orchestrate inflammatory processes. Here we review two major recent paradigm shifts in our understanding of tissue macrophage biology. The first is the realization that most tissue-resident macrophages are established prenatally and maintained through adulthood by longevity and self-renewal. Their generation and maintenance are thus independent from ongoing hematopoiesis, although the cells can be complemented by adult monocyte-derived macrophages. Second, aside from being immune sentinels, tissue macrophages form integral components of their host tissue. This entails their specialization in response to local environmental cues to contribute to the development and specific function of their tissue of residence. Factors that govern tissue macrophage specialization are emerging. Moreover, tissue specialization is reflected in discrete gene expression profiles of macrophages, as well as epigenetic signatures reporting actual and potential enhancer usage.


Asunto(s)
Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Diferenciación Celular , Humanos , Inmunidad , Macrófagos/clasificación , Macrófagos/citología , Especificidad de Órganos/inmunología , Fenotipo
2.
Immunity ; 53(3): 479-481, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32937148

RESUMEN

Liver macrophages play critical roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). In this issue of Immunity, Tran et al. and Remmerie et al. reveal that Ly6Chi monocytes in NASH replace dying resident Kupffer cells, while concomitantly are differentiating into distinct lipid associated macrophages.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Macrófagos del Hígado , Lípidos , Hígado , Monocitos
3.
Immunity ; 47(2): 219-221, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28813654

RESUMEN

Kupffer cells are recognized as the sole liver-resident macrophages responsible for clearance of blood-borne pathogens reaching liver sinusoids. Sierro et al. (2017) uncover a distinct liver-resident macrophage population residing in its capsule, which creates a firewall against peritoneal infections.


Asunto(s)
Macrófagos del Hígado , Macrófagos , Humanos , Hígado
4.
Am J Pathol ; 194(6): 941-957, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38493927

RESUMEN

Cholestatic injuries are accompanied by ductular reaction, initiated by proliferation and activation of biliary epithelial cells (BECs), leading to fibrosis. Sortilin (encoded by Sort1) facilitates IL-6 secretion and leukemia inhibitory factor (LIF) signaling. This study investigated the interplay between sortilin and IL-6 and LIF in cholestatic injury-induced ductular reaction, morphogenesis of new ducts, and fibrosis. Cholestatic injury was induced by bile duct ligation (BDL) in wild-type and Sort1-/- mice, with or without augmentation of IL-6 or LIF. Mice with BEC sortilin deficiency (hGFAPcre.Sort1fl/fl) and control mice were subjected to BDL and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet (DDC) induced cholestatic injury. Sort1-/- mice displayed reduced BEC proliferation and expression of BEC-reactive markers. Administration of LIF or IL-6 restored BEC proliferation in Sort1-/- mice, without affecting BEC-reactive or inflammatory markers. Sort1-/- mice also displayed impaired morphogenesis, which was corrected by LIF treatment. Similarly, hGFAPcre.Sort1fl/fl mice exhibited reduced BEC proliferation, but similar reactive and inflammatory marker expression. Serum IL-6 and LIF were comparable, yet liver pSTAT3 was reduced, indicating that sortilin is essential for co-activation of LIF receptor/gp130 signaling in BECs, but not for IL-6 secretion. hGFAPcre.Sortfl/fl mice displayed impaired morphogenesis and diminished fibrosis after BDL and DDC. In conclusion, sortilin-mediated engagement of LIF signaling in BECs promoted ductular reaction and morphogenesis during cholestatic injury. This study indicates that BEC sortilin is pivotal for the development of fibrosis.


Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular , Conductos Biliares , Colestasis , Células Epiteliales , Fibrosis , Animales , Ratones , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Conductos Biliares/patología , Proliferación Celular , Colestasis/patología , Colestasis/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Interleucina-6/metabolismo , Factor Inhibidor de Leucemia/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal
5.
Lab Invest ; 104(2): 100308, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38135154

RESUMEN

Obesity predisposes to metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, and type 2 diabetes. Accumulating evidence suggests a complex role of NLR family pyrin domain containing 3 (NLRP3) inflammasome function in multiple manifestations of the metabolic syndrome, with contradictory results. Its broad expression and pleiotropic functions during obesity led us to investigate the contribution of its expression in nonimmune versus immune cells to the development of obesity and MAFLD. Bone marrow chimerism was used to target NLRP3 deficiency to immune (ImmuneΔNlrp3) versus nonimmune (NonimmuneΔNlrp3) cells. Irradiated WT mice reconstituted with WT bone marrow served as controls. Mice were fed a 60% high-fat diet for 16 weeks. NonimmuneΔNlrp3 mice gained less weight and displayed reduced liver and epididymal white adipose tissue (epiWAT) mass. They also exhibited reduced adipocyte hypertrophy and increased epiWAT adipogenesis and lipolysis. Notable was the diminished hepatic steatosis in NonimmuneΔNlrp3 livers, which persisted even following equilibration of their body weight to that of the control. This was accompanied by a decline in liver triglycerides and in expression of transcriptional modules involved with lipid uptake, storage, and de novo lipogenesis. Thermogenic pathways in brown adipose tissue were comparable to control mice, but an elevation was observed in the genes encoding for lipid transporters and fatty acid oxidation. In contrast, deletion of NLRP3 in the immune cell compartment had limited effects on obesity and hepatic steatosis. Collectively, our results outline a prominent role for NLRP3 in nonimmune cells in facilitating MAFLD during constant energy surplus.


Asunto(s)
Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Inflamasomas/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Triglicéridos/metabolismo
6.
Allergy ; 78(2): 464-476, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36070083

RESUMEN

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, food-driven allergic disease, characterized by eosinophil-rich inflammation in the esophagus. The histopathological and clinical features of EoE have been attributed to overproduction of the type 2 cytokines IL-4 and IL-13, which mediate profound alterations in the esophageal epithelium and neutralizing of their shared receptor component (IL-4Rα) with a human antibody drug (dupilumab) demonstrates clinical efficacy. Yet, the relative contribution of IL-4 and IL-13 and whether the type II IL-4 receptor (comprised of the IL-4Rα chain in association with IL-13Rα1) mediates this effect has not been determined. METHODS: Experimental EoE was induced in WT, Il13ra1-/- , and Krt14Cre /Il13ra1fl/fl mice by skin-sensitized using 4-ethoxymethylene-2-phenyl-2-oxazolin (OXA) followed by intraesophageal challenges. Esophageal histopathology was determined histologically. RNA was extracted and sequenced for transcriptome analysis and compared with human EoE RNAseq data. RESULTS: Induction of experimental EoE in mice lacking Il13ra1 and in vivo IL-13 antibody-based neutralization experiments blocked antigen-induced esophageal epithelial and lamina propria thickening, basal cell proliferation, eosinophilia, and tissue remodeling. In vivo targeted deletion of Il13ra1 in esophageal epithelial cells rendered mice protected from experimental EoE. Single-cell RNA sequencing analysis of human EoE biopsies revealed predominant expression of IL-13Rα1 in epithelial cells and that EoE signature genes correlated with IL-13 expression compared with IL-4. CONCLUSIONS: We demonstrate a definitive role for IL-13 signaling via IL-13Rα1 in EoE. These data provide mechanistic insights into the mode of action of current therapies in EoE and highlight the type II IL-4R as a future therapeutic target.


Asunto(s)
Esofagitis Eosinofílica , Humanos , Ratones , Animales , Esofagitis Eosinofílica/patología , Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-13/metabolismo , Células Epiteliales/metabolismo
7.
Immunity ; 40(5): 720-33, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24792913

RESUMEN

Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome-wide association studies and experimental animal models point at a central role of the IL-10 axis in inflammatory bowel diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10Rα) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1-expressing macrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages and resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning agent in the colon and define intestinal CX3CR1(hi) macrophages as a decisive factor that determines gut health or inflammation.


Asunto(s)
Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Interleucina-10/inmunología , Macrófagos/inmunología , Receptores de Interleucina-10/inmunología , Animales , Receptor 1 de Quimiocinas CX3C , Células Cultivadas , Interleucina-10/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Quimiocina/biosíntesis , Receptores de Interleucina-10/genética , Linfocitos T Reguladores/inmunología
8.
Immunity ; 37(6): 1076-90, 2012 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-23219392

RESUMEN

Ly6C(hi) monocytes seed the healthy intestinal lamina propria to give rise to resident CX(3)CR1(+) macrophages that contribute to the maintenance of gut homeostasis. Here we report on two alternative monocyte fates in the inflamed colon. We showed that CCR2 expression is essential to the recruitment of Ly6C(hi) monocytes to the inflamed gut to become the dominant mononuclear cell type in the lamina propria during settings of acute colitis. In the inflammatory microenvironment, monocytes upregulated TLR2 and NOD2, rendering them responsive to bacterial products to become proinflammatory effector cells. Ablation of Ly6C(hi) monocytes ameliorated acute gut inflammation. With time, monocytes differentiated into migratory antigen-presenting cells capable of priming naive T cells, thus acquiring hallmarks reminiscent of dendritic cells. Collectively, our results highlight cellular dynamics in the inflamed colon and the plasticity of Ly6C(hi) monocytes, marking them as potential targets for inflammatory bowel disease (IBD) therapy.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Antígenos Ly/metabolismo , Movimiento Celular/inmunología , Colitis/inmunología , Monocitos/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Antígenos Ly/inmunología , Receptor 1 de Quimiocinas CX3C , Colitis/metabolismo , Colitis/patología , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Inmunofenotipificación , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Transgénicos , Monocitos/metabolismo , Proteína Adaptadora de Señalización NOD2/inmunología , Proteína Adaptadora de Señalización NOD2/metabolismo , Receptores CCR2/inmunología , Receptores CCR2/metabolismo , Receptores de Quimiocina/metabolismo , Linfocitos T/inmunología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 2/metabolismo
9.
J Immunol ; 198(8): 3089-3098, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-28250160

RESUMEN

The bone marrow (BM) contains controlled specialized microenvironments, or niches, that regulate the quiescence, proliferation, and differentiation of hematopoietic stem and progenitor cells (HSPC). The glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone that mediates postprandial insulin secretion and has anabolic effects on adipose tissue. Previous studies demonstrated altered bone microarchitecture in mice deficient for GIP receptor (Gipr-/- ), as well as the expression of high-affinity GIP receptor by distinct cells constructing the BM HSPC niche. Nevertheless, the involvement of GIP in the process of BM hematopoiesis remains elusive. In this article, we show significantly reduced representation and proliferation of HSPC and myeloid progenitors in the BM of Gipr-/- mice. This was further manifested by reduced levels of BM and circulating differentiated immune cells in young and old adult mice. Moreover, GIP signaling was required for the establishment of supportive BM HSPC niches during HSPC repopulation in radioablated BM chimera mice. Finally, molecular profiling of various factors involved in retention, survival, and expansion of HSPC revealed significantly lower expression of the Notch-receptor ligands Jagged 1 and Jagged 2 in osteoblast-enriched bone extracts from Gipr-/- mice, which are important for HSPC expansion. In addition, there was increased expression of CXCL12, a factor important for HSPC retention and quiescence, in whole-BM extracts from Gipr-/- mice. Collectively, our data suggest that the metabolic hormone GIP plays an important role in BM hematopoiesis.


Asunto(s)
Médula Ósea/metabolismo , Polipéptido Inhibidor Gástrico/metabolismo , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Animales , Citometría de Flujo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de la Hormona Gastrointestinal/deficiencia
10.
Immunity ; 31(3): 502-12, 2009 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-19733097

RESUMEN

The intestinal immune system discriminates between tolerance toward the commensal microflora and robust responses to pathogens. Maintenance of this critical balance is attributed to mucosal dendritic cells (DCs) residing in organized lymphoid tissue and dispersed in the subepithelial lamina propria. In situ parameters of lamina propria DCs (lpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that lpDC subsets have distinct origins and functions. CD103(+) CX(3)CR1(-) lpDCs arose from macrophage-DC precursors (MDPs) via DC-committed intermediates (pre-cDCs) through a Flt3L growth-factor-mediated pathway. CD11b(+) CD14(+) CX(3)CR1(+) lpDCs were derived from grafted Ly6C(hi) but not Ly6C(lo) monocytes under the control of GM-CSF. Mice reconstituted exclusively with CX(3)CR1(+) lpDCs when challenged in an innate colitis model developed severe intestinal inflammation that was driven by graft-derived TNF-alpha-secreting CX(3)CR1(+) lpDCs. Our results highlight the critical importance of the lpDC subset balance for robust gut homeostasis.


Asunto(s)
Linaje de la Célula , Células Dendríticas/citología , Células Dendríticas/inmunología , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Animales , Antígenos CD/inmunología , Antígeno CD11b/inmunología , Diferenciación Celular , Línea Celular Tumoral , Colitis/inmunología , Colitis/patología , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Homeostasis , Cadenas alfa de Integrinas/inmunología , Ratones , Ratones Endogámicos C57BL , Fenotipo , Receptores de Interleucina-8A/inmunología , Tirosina Quinasa 3 Similar a fms/inmunología
11.
Surg Innov ; 24(2): 139-144, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28152672

RESUMEN

BACKGROUND: Tumor localization may pose a significant challenge during minimally invasive rectal resection. Near-infrared (NIR) imaging can penetrate biological tissue and afford tumor localization from the external surface of the rectum. Our aim was to develop an NIR-based tool for rectal tumor imaging that can be administered intravenously. METHODS: We prepared indocyanine-green (ICG)-loaded liposomes by sonication. Liposomes were evaluated for their size and morphology. We then used an endoscopically induced rectal cancer in mice as a model for rectal cancer. After intravenous administration, tumors were evaluated for their fluorescence intensity. Tumor intensity was expressed in relation to the background signal, that is, tumor to background ratio (TBR). RESULTS: Liposomes in various sizes could be prepared by adjusting sonication time. We selected 100-nm-sized liposomes for further experiments. Transmission electron microscopy showed spherical particles and confirmed the size measurements. The liposomes could be lyophilized and then rehydrated again before use without compromising their structure or signal. Fluorescence intensity was kept for 24 hours after solubilization. Testing the optimal time course for rectal tumor imaging revealed that early time course (up to 3 hours) yielded nonspecific imaging, whereas after long time course (24 hours), a very weak signal remained in the tissue. The optimal time window for imaging was after 12 hours from injection, with TBR = 8.1 ± 3.6 ( P = .002). Free ICG could not achieve similar results. CONCLUSIONS: The liposomal ICG can be reproducibly prepared and kept in lyophilized form. Liposomal ICG could serve as a tool for intraoperative tumor localization.


Asunto(s)
Verde de Indocianina/uso terapéutico , Laparoscopía/métodos , Liposomas/uso terapéutico , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/cirugía , Cirugía Asistida por Computador/métodos , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Espectroscopía Infrarroja Corta
12.
J Immunol ; 193(1): 344-53, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24890723

RESUMEN

The liver has a remarkable capacity to regenerate after injury; yet, the role of macrophages (MF) in this process remains controversial mainly due to difficulties in distinguishing between different MF subsets. In this study, we used a murine model of acute liver injury induced by overdose of N-acetyl-p-aminophenol (APAP) and defined three distinct MF subsets that populate the liver following injury. Accordingly, resident Kupffer cells (KC) were significantly reduced upon APAP challenge and started recovering by self-renewal at resolution phase without contribution of circulating Ly6C(hi) monocytes. The latter were recruited in a CCR2- and M-CSF-mediated pathway at the necroinflammatory phase and differentiated into ephemeral Ly6C(lo) MF subset at resolution phase. Moreover, their inducible ablation resulted in impaired recovery. Microarray-based molecular profiling uncovered high similarity between steady-state KC and those recovered at the resolution phase. In contrast, KC and monocyte-derived MF displayed distinct prorestorative genetic signature at the resolution phase. Finally, we show that infiltrating monocytes acquire a prorestorative polarization manifested by unique expression of proangiogenesis mediators and genes involved with inhibition of neutrophil activity and recruitment and promotion of their clearance. Collectively, our results present a novel phenotypic, ontogenic, and molecular definition of liver-MF compartment following acute injury.


Asunto(s)
Acetaminofén/efectos adversos , Analgésicos no Narcóticos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Macrófagos del Hígado/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Acetaminofén/farmacología , Enfermedad Aguda , Analgésicos no Narcóticos/farmacología , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Macrófagos del Hígado/patología , Hígado/inmunología , Hígado/lesiones , Hígado/patología , Macrófagos/patología , Ratones , Ratones Noqueados , Monocitos/patología
13.
J Immunol ; 193(8): 4002-9, 2014 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-25217161

RESUMEN

Obesity induces low-grade chronic inflammation, manifested by proinflammatory polarization of adipose tissue innate and adaptive resident and recruited immune cells that contribute to insulin resistance (IR). The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that mediates postprandial insulin secretion and has anabolic effects on the adipose tissue. Importantly, recent evidence suggested that GIP is a potential suppressor of inflammation in several metabolic models. In this study, we aimed to investigate the immunoregulatory role of GIP in a murine model of diet-induced obesity (DIO) using the long-acting GIP analog [d-Ala(2)]GIP. Administration of [d-Ala(2)]GIP resulted in adipocytes of increased size, increased levels of adipose tissue lipid droplet proteins, indicating better lipid storage capacity, and reduced adipose tissue inflammation. Flow cytometry analysis revealed reduced numbers of inflammatory Ly6C(hi) monocytes and F4/80(hi)CD11c(+) macrophages, associated with IR. In addition, [d-Ala(2)]GIP reduced adipose tissue infiltration of IFN-γ-producing CD8(+) and CD4(+) T cells. Furthermore, [d-Ala(2)]GIP treatment induced a favorable adipose tissue adipokine profile, manifested by a prominent reduction in key inflammatory cytokines (TNF-α, IL-1ß, IFN-γ) and chemokines (CCL2, CCL8, and CCL5) and an increase in adiponectin. Notably, [d-Ala(2)]GIP also reduced the numbers of circulating neutrophils and proinflammatory Ly6C(hi) monocytes in mice fed regular chow or a high-fat diet. Finally, the beneficial immune-associated effects were accompanied by amelioration of IR and improved insulin signaling in liver and adipose tissue. Collectively, our results describe key beneficial immunoregulatory properties for GIP in DIO and reveal that its augmentation ameliorates adipose tissue inflammation and improves IR.


Asunto(s)
Tejido Adiposo/efectos de los fármacos , Polipéptido Inhibidor Gástrico/uso terapéutico , Resistencia a la Insulina/inmunología , Obesidad/tratamiento farmacológico , Adipocitos/patología , Adiponectina/biosíntesis , Tejido Adiposo/inmunología , Tejido Adiposo/patología , Animales , Antígenos de Diferenciación/metabolismo , Antígenos Ly/metabolismo , Glucemia , Antígeno CD11c/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocina CCL2/biosíntesis , Quimiocina CCL5/biosíntesis , Quimiocina CCL8/biosíntesis , Dieta Alta en Grasa , Humanos , Insulina/metabolismo , Secreción de Insulina , Interferón gamma/biosíntesis , Interleucina-1beta/biosíntesis , Gotas Lipídicas/patología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Neutrófilos/inmunología , Obesidad/patología , Receptores de la Hormona Gastrointestinal/inmunología , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis
14.
Gastroenterology ; 147(1): 184-195.e3, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24727021

RESUMEN

BACKGROUND & AIMS: Activation of the transcription factor nuclear factor-κB (NF-κB) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-κB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings. METHODS: We created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-κB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. RESULTS: In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. CONCLUSIONS: Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Colitis/prevención & control , Colitis/fisiopatología , Neoplasias del Colon/prevención & control , Neoplasias del Colon/fisiopatología , Inflamación/genética , Inflamación/fisiopatología , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Azoximetano/efectos adversos , Biopsia , Estudios de Casos y Controles , Colitis/inducido químicamente , Colon/metabolismo , Colon/patología , Neoplasias del Colon/inducido químicamente , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/metabolismo
15.
J Exp Med ; 204(1): 171-80, 2007 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-17190836

RESUMEN

The mononuclear phagocyte (MP) system is a body-wide macrophage (MPhi) and dendritic cell (DC) network, which contributes to tissue homeostasis, inflammation, and immune defense. The in vivo origins of MPs remain poorly understood. Here, we use an adoptive precursor cell transfer strategy into MP-depleted mice to establish the in vivo differentiation sequence from a recently identified MPhi/DC-restricted bone marrow (BM) precursor (MDP) via BM and blood intermediates to peripheral MPhis and DCs. We show that MDPs are in vivo precursors of BM and blood monocytes. Interestingly, grafted Gr1high "inflammatory" blood monocytes shuttle back to the BM in the absence of inflammation, convert into Gr1low monocytes, and contribute further to MP generation. The grafted monocytes give rise to DCs in the intestinal lamina propria and lung, but not to conventional CD11chigh DCs in the spleen, which develop during homeostasis from MDPs without a monocytic intermediate.


Asunto(s)
Células Dendríticas/citología , Células Dendríticas/inmunología , Monocitos/citología , Monocitos/inmunología , Traslado Adoptivo , Animales , Diferenciación Celular , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Pulmón/citología , Pulmón/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Ratones Transgénicos , Membrana Mucosa/citología , Membrana Mucosa/inmunología , Bazo/citología , Bazo/inmunología
16.
J Biol Chem ; 286(6): 4429-42, 2011 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-21119198

RESUMEN

Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.


Asunto(s)
Sustitución de Aminoácidos , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Leptina/análogos & derivados , Mutación Missense , Polietilenglicoles , Animales , Células HEK293 , Humanos , Leptina/antagonistas & inhibidores , Leptina/química , Leptina/genética , Leptina/metabolismo , Leptina/farmacología , Masculino , Ratones , Mutagénesis , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Polietilenglicoles/farmacología , Unión Proteica , Receptores de Leptina/genética , Receptores de Leptina/metabolismo
17.
Front Immunol ; 12: 643144, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33717200

RESUMEN

Glucose-dependent insulinotropic polypeptide (GIP) communicates information on energy availability from the gut to peripheral tissues. Disruption of its signaling in myeloid immune cells during high-fat diet (HFD)-induced obesity impairs energy homeostasis due to the unrestrained metabolically deleterious actions of S100A8/A9 alarmin. White adipose tissue (WAT) type 2 immune cell networks are important for maintaining metabolic and energy homeostasis and limiting obesity-induced inflammation. Nevertheless, the consequences of losing immune cell GIP receptor (GIPR) signaling on type 2 immunity in WAT remains unknown. Bone marrow (BM) chimerism was used to generate mice with GIPR (Gipr-/- BM) and GIPR/S100A8/A9 (Gipr-/- /S100a9-/- BM) deletion in immune cells. These mice were subjected to short (5 weeks) and progressive (14 weeks) HFD regimens. GIPR-deficiency was also targeted to myeloid cells by crossing Giprfl/fl mice and Lyz2cre/+ mice (LysMΔGipr ). Under both short and progressive HFD regimens, Gipr-/- BM mice exhibited altered expression of key type 2 immune cytokines in the epididymal visceral WAT (epiWAT), but not in subcutaneous inguinal WAT. This was further linked to declined representation of type 2 immune cells in epiWAT, such as group 2 innate lymphoid cells (ILC2), eosinophils, and FOXP3+ regulatory T cells (Tregs). Co-deletion of S100A8/A9 in Gipr-/- immune cells reversed the impairment of type 2 cytokine expression in epiWAT, suggesting a mechanistic role for this alarmin in type 2 immune suppression. LysMΔGipr mice on HFD also displayed altered expression of type 2 immune mediators, highlighting that GIPR-deficiency in myeloid immune cells is responsible for the impairment of type 2 immune networks. Finally, abrogated GIPR signaling in immune cells also affected adipocyte fraction cells, inducing their increased production of the beiging interfering cytokine IL-10 and stress- related type 2 cytokine IL-13. Collectively, these findings attribute an important role for GIPR in myeloid immune cells in supporting WAT type 2 immunity.


Asunto(s)
Tejido Adiposo Blanco/inmunología , Linfocitos/inmunología , Obesidad/inmunología , Receptores de la Hormona Gastrointestinal/fisiología , Tejido Adiposo Blanco/metabolismo , Animales , Calgranulina A/fisiología , Calgranulina B/fisiología , Dieta Alta en Grasa , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Transducción de Señal/fisiología , Termogénesis
18.
Cell Rep ; 37(7): 110026, 2021 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-34788631

RESUMEN

Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6Chi monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6Chi monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6Chi monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire "neutrophil-like" and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos del Hígado/metabolismo , Animales , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Diferenciación Celular/genética , Supervivencia Celular , Hematopoyesis , Inflamasomas/metabolismo , Inflamación/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Macrófagos del Hígado/fisiología , Hígado/citología , Hígado/lesiones , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismo
19.
Matrix Biol ; 96: 47-68, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33246101

RESUMEN

Identification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular-matrix dynamics during disease onset, while treating the matrix as a complete and defined entity. Through the analysis of matrix structure, stiffness and composition, we unexpectedly revealed that even prior to the first clinical symptoms, the colon displays its own unique extracellular-matrix signature and found specific markers of clinical potential, which were also validated in human subjects. We also show that the emergence of this pre-symptomatic matrix is mediated by subclinical infiltration of immune cells bearing remodeling enzymes. Remarkably, whether the inflammation is chronic or acute, its matrix signature converges at pre-symptomatic states. We suggest that the existence of a pre-symptomatic extracellular-matrix is general and relevant to a wide range of diseases.


Asunto(s)
Biomarcadores/metabolismo , Colitis Ulcerosa/patología , Matriz Extracelular/patología , Interleucina-10/genética , Animales , Estudios de Casos y Controles , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Matriz Extracelular/ultraestructura , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Aprendizaje Automático , Masculino , Ratones , Piroxicam/efectos adversos , Pronóstico , Proteómica
20.
Front Immunol ; 11: 1592, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32849539

RESUMEN

Cholesterol-laden, foam macrophages constitute the most characteristic component of human atherosclerotic plaques. Persistent uptake of oxLDLs results in accumulation of lipid bodies inside the cells and determines their phenotype and subsequent functions. In this work, we describe the phenotype of human monocyte-derived foam cells obtained by differentiation in the constant presence of oxLDLs for 30 days (prolonged-hMDFCs). Although neither the total cellular nor the cell surface expression of Toll-like receptors (TLR) was regulated by oxLDLs, the prolonged-hMDFCs changed dramatically their responsiveness to TLR ligands and inactivated bacteria. Using multiplex technology, we observed an acute decline in cytokine and chemokine production after surface and endosomal TLR stimulation with the exception of TLR2/6 triggering with agonists Pam2CSK4 and MALP-2. We also noted significant reduction of some surface receptors which can have accessory function in recognition of particulate antigens (CD47, CD81, and CD11b). In contrast, the prolonged-hMDFCs responded to inflammasome activation by LPS/nigericin with extensive, necrotic type cell death, which was partially independent of caspase-1. This pyroptosis-like cell death was aggravated by necrostatin-1 and rapamycin. These findings identify a potential contribution of mature foam cells to inflammatory status by increasing the immunogenic cell death burden. The observed cross-talk between foam cell death pathways may lead to recognition of a potential new marker for atherosclerosis disease severity. Overall, our study demonstrates that, in contrast to other cellular models of foam cells, the prolonged-hMDFCs acquire a functional phenotype which may help understanding the role of foam cells in the pathogenesis of atherosclerosis.


Asunto(s)
Células Espumosas/inmunología , Células Espumosas/metabolismo , Interacciones Huésped-Patógeno , Lipoproteínas LDL/metabolismo , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismo , Fenotipo , Biomarcadores , Células Cultivadas , Citocinas/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Inflamasomas/metabolismo , Mediadores de Inflamación/metabolismo , Monocitos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis/inmunología
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