RESUMEN
Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.
Asunto(s)
Quitinasas/inmunología , Tracto Gastrointestinal/inmunología , Inmunidad/inmunología , Infecciones por Strongylida/inmunología , Animales , Quitinasas/genética , Quitinasas/metabolismo , Canales de Cloruro/genética , Canales de Cloruro/inmunología , Canales de Cloruro/metabolismo , Citometría de Flujo , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/parasitología , Expresión Génica/inmunología , Hormonas Ectópicas/genética , Hormonas Ectópicas/inmunología , Hormonas Ectópicas/metabolismo , Interacciones Huésped-Parásitos/inmunología , Hipersensibilidad/genética , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Inmunidad/genética , Péptidos y Proteínas de Señalización Intercelular , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-13/metabolismo , Lectinas/genética , Lectinas/inmunología , Lectinas/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Fluorescente , Nematospiroides dubius/inmunología , Nematospiroides dubius/fisiología , Nippostrongylus/inmunología , Nippostrongylus/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Infecciones por Strongylida/metabolismo , Infecciones por Strongylida/parasitología , beta-N-Acetilhexosaminidasas/genética , beta-N-Acetilhexosaminidasas/inmunología , beta-N-Acetilhexosaminidasas/metabolismoRESUMEN
Fibrosis can affect any organ and is responsible for up to 45% of all deaths in the industrialized world. It has long been thought to be relentlessly progressive and irreversible, but both preclinical models and clinical trials in various organ systems have shown that fibrosis is a highly dynamic process. This has clear implications for therapeutic interventions that are designed to capitalize on this inherent plasticity. However, despite substantial progress in our understanding of the pathobiology of fibrosis, a translational gap remains between the identification of putative antifibrotic targets and conversion of this knowledge into effective treatments in humans. Here we discuss the transformative experimental strategies that are being leveraged to dissect the key cellular and molecular mechanisms that regulate fibrosis, and the translational approaches that are enabling the emergence of precision medicine-based therapies for patients with fibrosis.
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Fibrosis/tratamiento farmacológico , Fibrosis/patología , Citocinas , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis/genética , Fibrosis/metabolismo , Microbioma Gastrointestinal , Genoma Humano/genética , Humanos , Integrinas , Macrófagos , Mesodermo/metabolismo , Mesodermo/patología , Medicina de Precisión , Análisis de la Célula Individual , Factor de Crecimiento Transformador beta , Investigación Biomédica TraslacionalRESUMEN
Inflammatory monocytes and tissue-resident macrophages are key regulators of tissue repair, regeneration, and fibrosis. After tissue injury, monocytes and macrophages undergo marked phenotypic and functional changes to play critical roles during the initiation, maintenance, and resolution phases of tissue repair. Disturbances in macrophage function can lead to aberrant repair, such that uncontrolled production of inflammatory mediators and growth factors, deficient generation of anti-inflammatory macrophages, or failed communication between macrophages and epithelial cells, endothelial cells, fibroblasts, and stem or tissue progenitor cells all contribute to a state of persistent injury, and this could lead to the development of pathological fibrosis. In this review, we discuss the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound-healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue-regenerating phenotypes after injury, and we highlight how some of these mechanisms and macrophage activation states could be exploited therapeutically.
Asunto(s)
Macrófagos/fisiología , Regeneración , Cicatrización de Heridas , Animales , Comunicación Celular , Diferenciación Celular , Fibrosis , Humanos , Activación de Macrófagos , Macrófagos/patología , FenotipoRESUMEN
Neutrophils are the first immune cells recruited to sites of inflammation and infection. However, patients with allergic disorders such as atopic dermatitis show a paucity of skin neutrophils and are prone to bacterial skin infections, suggesting that allergic inflammation curtails neutrophil responses. Here we have shown that the type 2 cell signature cytokine interleukin-4 (IL-4) hampers neutrophil expansion and migration by antagonizing granulocyte colony-stimulating factor (G-CSF) and chemokine receptor-mediated signals. Cutaneous bacterial infection in mice was exacerbated by IL-4 signaling and improved with IL-4 inhibition, each outcome inversely correlating with neutrophil migration to skin. Likewise, systemic bacterial infection was worsened by heightened IL-4 activity, with IL-4 restricting G-CSF-induced neutrophil expansion and migration to tissues by affecting CXCR2-CXCR4 chemokine signaling in neutrophils. These effects were dependent on IL-4 acting through type 2 IL-4 receptors on neutrophils. Thus, targeting IL-4 might be beneficial in neutropenic conditions with increased susceptibility to bacterial infections.
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Inflamación/inmunología , Listeria monocytogenes/fisiología , Listeriosis/inmunología , Neutrófilos/inmunología , Receptores de Superficie Celular/metabolismo , Infecciones Estreptocócicas/inmunología , Streptococcus pyogenes/fisiología , Animales , Carga Bacteriana , Movimiento Celular , Proliferación Celular , Células Cultivadas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Superficie Celular/genética , Transducción de Señal , Células Th2/inmunologíaRESUMEN
Fibroproliferative diseases are driven by dysregulated tissue repair responses and are a major cause of morbidity and mortality because they affect nearly every organ system. Type 2 cytokine responses are critically involved in tissue repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis are not well understood. Here, we have shown that the type 2 effector cytokine interleukin-13 simultaneously, yet independently, directed hepatic fibrosis and the compensatory proliferation of hepatocytes and biliary cells in progressive models of liver disease induced by interleukin-13 overexpression or after infection with Schistosoma mansoni. Using transgenic mice with interleukin-13 signaling genetically disrupted in hepatocytes, cholangiocytes, or resident tissue fibroblasts, we have revealed direct and distinct roles for interleukin-13 in fibrosis, steatosis, cholestasis, and ductular reaction. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis. VIDEO ABSTRACT.
Asunto(s)
Hígado Graso/inmunología , Fibroblastos/inmunología , Interleucina-13/metabolismo , Cirrosis Hepática Biliar/inmunología , Hígado/patología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Animales , Ácidos y Sales Biliares/biosíntesis , Proliferación Celular , Células Cultivadas , Fibrosis , Humanos , Interleucina-13/genética , Interleucina-13/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Células Th2/inmunologíaRESUMEN
BACKGROUND & AIMS: Fibroblasts play a key role in stricture formation in Crohn's disease (CD) but understanding its pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full-thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single-cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. METHODS: We performed scRNAseq of 13 fresh full-thickness CD resections containing noninvolved, inflamed nonstrictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 99 tissue samples and 409,001 cells. We validated cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next-generation sequencing, proteomics, and animal models. RESULTS: Our integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture-selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and up-regulated, and its profibrotic function was validated using NanoString nCounter, RNA sequencing, tissue target expression, in vitro gain- and loss-of-function experiments, proteomics, and knock-out and antibody-mediated CDH11 blockade in experimental colitis. CONCLUSIONS: A full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and open potential therapeutic developments. This work has been posted as a preprint on Biorxiv under doi: 10.1101/2023.04.03.534781.
Asunto(s)
Colitis , Enfermedad de Crohn , Animales , Enfermedad de Crohn/genética , Enfermedad de Crohn/patología , Constricción Patológica , Intestinos/patología , Colitis/patología , Fibroblastos/patologíaRESUMEN
Hematopoietic cells, including lymphoid and myeloid cells, can develop into phenotypically distinct 'subpopulations' with different functions. However, evidence indicates that some of these subpopulations can manifest substantial plasticity (that is, undergo changes in their phenotype and function). Here we focus on the occurrence of phenotypically distinct subpopulations in three lineages of myeloid cells with important roles in innate and acquired immunity: macrophages, mast cells and neutrophils. Cytokine signals, epigenetic modifications and other microenvironmental factors can substantially and, in some cases, rapidly and reversibly alter the phenotype of these cells and influence their function. This suggests that regulation of the phenotype and function of differentiated hematopoietic cells by microenvironmental factors, including those generated during immune responses, represents a common mechanism for modulating innate or adaptive immunity.
Asunto(s)
Citocinas/inmunología , Inmunidad Innata , Macrófagos/metabolismo , Mastocitos/metabolismo , Neutrófilos/metabolismo , Inmunidad Adaptativa , Animales , Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Epigénesis Genética/inmunología , Regulación de la Expresión Génica/inmunología , Humanos , Macrófagos/citología , Macrófagos/inmunología , Mastocitos/citología , Mastocitos/inmunología , Células Progenitoras Mieloides/citología , Neutrófilos/citología , Neutrófilos/inmunología , Transducción de Señal/inmunología , Nicho de Células Madre/inmunologíaRESUMEN
Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation-with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature.
Asunto(s)
Activación de Macrófagos/inmunología , Macrófagos/inmunología , Terminología como Asunto , Animales , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Guías como Asunto , Humanos , Factor Estimulante de Colonias de Macrófagos/inmunología , Ratones , InvestigaciónRESUMEN
BACKGROUND AND AIMS: Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (extrahepatic bile ducts; EHBDs) or inside the liver (intrahepatic bile ducts; IHBDs). These organoids share many characteristics, including expression of cholangiocyte markers such as keratin (KRT) 19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown. APPROACH AND RESULTS: Organoids were derived from human gallbladder, common bile duct, pancreatic duct, and IHBDs using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers leucine-rich repeat-containing G-protein-coupled receptor 5/prominin 1 and ductal markers KRT19/KRT7. However, RNA sequencing revealed that organoids conserve only a limited number of regional-specific markers corresponding to their location of origin. Of particular interest, down-regulation of biliary markers and up-regulation of cell-cycle genes were observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling, and only IHBDs were able to express a low level of hepatocyte markers under differentiation conditions. CONCLUSIONS: Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin, but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify targets for therapeutic development.
Asunto(s)
Conductos Biliares Extrahepáticos/citología , Conductos Biliares Intrahepáticos/citología , Células Epiteliales/citología , Organoides/fisiología , Animales , Bilis , Conductos Biliares Extrahepáticos/fisiología , Conductos Biliares Intrahepáticos/fisiología , Diferenciación Celular , Conducto Colédoco/citología , Células Epiteliales/fisiología , Vesícula Biliar/citología , Regulación de la Expresión Génica , Humanos , Queratina-19/análisis , Hígado/fisiología , Ratones , RNA-Seq , Obtención de Tejidos y ÓrganosRESUMEN
Metabolic reprogramming plays a central role in T cell activation and differentiation, and the inhibition of key metabolic pathways in activated T cells represents a logical approach for the development of new therapeutic agents for treating autoimmune diseases. The widely prescribed antidiabetic drug metformin and the glycolytic inhibitor 2-deoxyglucose (2-DG) have been used to study the inhibition of oxidative phosphorylation and glycolysis, respectively, in murine immune cells. Published studies have demonstrated that combination treatment with metformin and 2-DG was efficacious in dampening mouse T cell activation-induced effector processes, relative to treatments with either metformin or 2-DG alone. In this study, we report that metformin + 2-DG treatment more potently suppressed IFN-γ production and cell proliferation in activated primary human CD4+ T cells than either metformin or 2-DG treatment alone. The effects of metformin + 2-DG on human T cells were accompanied by significant remodeling of activation-induced metabolic transcriptional programs, in part because of suppression of key transcriptional regulators MYC and HIF-1A. Accordingly, metformin + 2-DG treatment significantly suppressed MYC-dependent metabolic genes and processes, but this effect was found to be independent of mTORC1 signaling. These findings reveal significant insights into the effects of metabolic inhibition by metformin + 2-DG treatment on primary human T cells and provide a basis for future work aimed at developing new combination therapy regimens that target multiple pathways within the metabolic networks of activated human T cells.
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Linfocitos T CD4-Positivos/efectos de los fármacos , Desoxiglucosa/farmacología , Redes y Vías Metabólicas/efectos de los fármacos , Metformina/farmacología , Animales , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Glucólisis/efectos de los fármacos , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Fosforilación Oxidativa/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Dendritic cells are best known as antigen-presenting cells that initiate adaptive immune responses. Three new papers suggest that basophils initiate allergen- and helminth-driven CD4+ T helper type 2 responses by functioning as antigen-presenting cells in draining lymph nodes.
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Células Presentadoras de Antígenos/inmunología , Basófilos/inmunología , Células Dendríticas/inmunología , Células Th2/inmunología , Animales , Antígenos Helmínticos/inmunología , Modelos InmunológicosRESUMEN
Macrophages regulate tissue regeneration following injury. They can worsen tissue injury by producing reactive oxygen species and other toxic mediators that disrupt cell metabolism, induce apoptosis, and exacerbate ischemic injury. However, they also produce a variety of growth factors, such as IGF-1, VEGF-α, TGF-ß, and Wnt proteins that regulate epithelial and endothelial cell proliferation, myofibroblast activation, stem and tissue progenitor cell differentiation, and angiogenesis. Proresolving macrophages in turn restore tissue homeostasis by functioning as anti-inflammatory cells, and macrophage-derived matrix metalloproteinases regulate fibrin and collagen turnover. However, dysregulated macrophage function impairs wound healing and contributes to the development of fibrosis. Consequently, the mechanisms that regulate these different macrophage activation states have become active areas of research. In this review, we discuss the common and unique mechanisms by which macrophages instruct tissue repair in the liver, nervous system, heart, lung, skeletal muscle, and intestine and illustrate how macrophages might be exploited therapeutically.
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Macrófagos/fisiología , Regeneración/fisiología , Cicatrización de Heridas/fisiología , Animales , Diferenciación Celular/fisiología , Homeostasis/fisiología , HumanosRESUMEN
Heat shock proteins (Hsps) are highly conserved molecular chaperones that are ubiquitously expressed in all species to aid the solubilization of misfolded proteins, protein degradation, and transport. Elevated levels of Hsp70 have been found in the sputum, serum, and bronchoalveolar lavage (BAL) fluid of asthma patients and are known to correlate with disease severity. However, the function of Hsp70 in allergic airway inflammation has remained largely unknown. This study aimed to determine the role of Hsp70 in airway inflammation and remodeling using a mouse model of allergic airway inflammation. WT and Hsp70 double-knockout (Hsp70.1/.3-/-) mice were sensitized and challenged intratracheally with Schistosoma mansoni soluble egg antigens (SEAs) to induce robust Th2 responses and airway inflammation in the lungs. The lack of Hsp70 resulted in a significant reduction in airway inflammation, goblet cell hyperplasia, and Th2 cytokine production, including IL-4, IL-5, and IL-13. An analysis of the BAL fluid suggested that Hsp70 is critically required for eosinophilic infiltration, collagen accumulation, and Th2 cytokine production in allergic airways. Furthermore, our bone marrow (BM) transfer studies show that SEA-induced airway inflammation, goblet cell hyperplasia, and Th2 cytokine production were attenuated in WT mice that were reconstituted with Hsp70-deficient BM, but these effects were not attenuated in Hsp70-deficient mice that were reconstituted with WT BM. Together, these studies identify a pathogenic role for Hsp70 in hematopoietic cells during allergic airway inflammation; this illustrates the potential utility of targeting Hsp70 to alleviate allergen-induced Th2 cytokines, goblet cell hyperplasia, and airway inflammation.
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Células Caliciformes/patología , Proteínas HSP70 de Choque Térmico/metabolismo , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Pulmón/patología , Animales , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Redes Reguladoras de Genes , Hiperplasia/metabolismo , Hipersensibilidad/genética , Hipersensibilidad/inmunología , Pulmón/inmunología , Pulmón/metabolismo , Ratones , Células Th2/inmunologíaRESUMEN
Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.
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Péptidos y Proteínas de Señalización Intercelular/metabolismo , Lectinas/metabolismo , Infecciones por Nematodos/metabolismo , Receptores de Superficie Celular/deficiencia , beta-N-Acetilhexosaminidasas/metabolismo , Animales , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/parasitología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Nematodos/inmunología , Nippostrongylus/inmunología , Receptores de Superficie Celular/metabolismo , Transducción de Señal , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/metabolismoRESUMEN
The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (T(H)2)-mediated disease and associates with either the common gamma-chain to form the type I IL-4R or with the IL-13R alpha1 chain (IL-13Ralpha1) to form the type II IL-4R. Here we used Il13ra1-/- mice to characterize the distinct functions of type I and type II IL-4 receptors in vivo. In contrast to Il4ra-/- mice, which have weak T(H)2 responses, Il13ra1-/- mice had exacerbated T(H)2 responses. Il13ra1-/- mice showed much less mortality after infection with Schistosoma mansoni and much more susceptibility to Nippostrongylus brasiliensis. IL-13Ralpha1 was essential for allergen-induced airway hyperreactivity and mucus hypersecretion but not for fibroblast or alternative macrophage activation. Thus, type I and II IL-4 receptors exert distinct effects on immune responses.
Asunto(s)
Subunidad alfa1 del Receptor de Interleucina-13/fisiología , Receptores Tipo II de Interleucina-4/fisiología , Células Th2/inmunología , Alérgenos/inmunología , Animales , Antígenos Helmínticos/inmunología , Hiperreactividad Bronquial/inmunología , Células Cultivadas , Susceptibilidad a Enfermedades , Fibroblastos/inmunología , Subunidad alfa1 del Receptor de Interleucina-13/genética , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Moco/metabolismo , Nippostrongylus/fisiología , Schistosoma mansoni/inmunología , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/mortalidad , Infecciones por Strongylida/inmunologíaRESUMEN
Toll-like receptor (TLR) signaling in macrophages is required for antipathogen responses, including the biosynthesis of nitric oxide from arginine, and is essential for immunity to Mycobacterium tuberculosis, Toxoplasma gondii and other intracellular pathogens. Here we report a 'loophole' in the TLR pathway that is advantageous to these pathogens. Intracellular pathogens induced expression of the arginine hydrolytic enzyme arginase 1 (Arg1) in mouse macrophages through the TLR pathway. In contrast to diseases dominated by T helper type 2 responses in which Arg1 expression is greatly increased by interleukin 4 and 13 signaling through the transcription factor STAT6, TLR-mediated Arg1 induction was independent of the STAT6 pathway. Specific elimination of Arg1 in macrophages favored host survival during T. gondii infection and decreased lung bacterial load during tuberculosis infection.
Asunto(s)
Arginasa/inmunología , Infecciones Bacterianas/inmunología , Macrófagos/inmunología , Macrófagos/microbiología , Receptores Toll-Like/inmunología , Animales , Arginasa/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/inmunología , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Immunoblotting , Inmunohistoquímica , Ratones , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Factor de Transcripción STAT6/inmunología , Factor de Transcripción STAT6/metabolismo , Receptores Toll-Like/metabolismoRESUMEN
Immune tolerance is defined by an active state of immune system unresponsiveness to foreign and self-antigens. Loss of immune tolerance to self-antigens and the resulting overexpression of autoantibodies can lead to tissue injury and development of various autoimmune diseases. In drug development, the goal of newly emerging immune tolerance therapies is to treat autoimmune disorders by restoring the immunoregulatory capacity of the immune system. Development of immune tolerance targets is initiated with the establishment of pharmacological efficacy in relevant disease animal models, followed by their stepwise translation to humans. This review discusses the major challenges to developing tolerance inducing pharmaceutical drugs, including the selection of appropriate disease models to establish efficacy, adequate, and acceptable in vitro and in vivo safety assessments, relevant biomarkers of human safety and efficacy, and finally, some regulatory guidelines to successfully develop immune tolerance therapeutics. [Box: see text].
Asunto(s)
Enfermedades Autoinmunes , Tolerancia Inmunológica , Animales , Autoanticuerpos , Enfermedades Autoinmunes/tratamiento farmacológico , HumanosRESUMEN
Fibroproliferative diseases affect a significant proportion of the world's population. Despite this, core mechanisms driving organ fibrosis of diverse etiologies remain ill defined. Recent studies suggest that integrin-alpha V serves as a master driver of fibrosis in multiple organs. Although diverse mechanisms contribute to the progression of fibrosis, TGF-ß and IL-13 have emerged as central mediators of fibrosis during type 1/type 17, and type 2 polarized inflammatory responses, respectively. To investigate if integrin-alpha V interactions or signaling is critical to the development of type 2 fibrosis, we analyzed fibroblast-specific integrin-alpha V knockout mice in three type 2-driven inflammatory disease models. While we confirmed a role for integrin-alpha V in type 17-associated fibrosis, integrin-alpha V was not critical to the development of type 2-driven fibrosis. Additionally, our studies support a novel mechanism through which fibroblasts, via integrin-alpha V expression, are capable of regulating immune polarization. We show that when integrin-alpha V is deleted on fibroblasts, initiation of type 17 inflammation is inhibited leading to a deregulation of type 2 inflammation. This mechanism is most evident in a model of severe asthma, which is characterized by a mixed type 2/type 17 inflammatory response. Together, these findings suggest dual targeting of integrin-alpha V and type 2 pathways may be needed to ameliorate fibrosis and prevent rebound of opposing pro-fibrotic and inflammatory mechanisms. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.