RESUMEN
Adequate mass and function of adipose tissues (ATs) play essential roles in preventing metabolic perturbations. The pathological reduction of ATs in lipodystrophy leads to an array of metabolic diseases. Understanding the underlying mechanisms may benefit the development of effective therapies. Several cellular processes, including autophagy and vesicle trafficking, function collectively to maintain AT homeostasis. Here, we investigated the impact of adipocyte-specific deletion of the lipid kinase phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) on AT homeostasis and systemic metabolism in mice. We report that PIK3C3 functions in all ATs and that its absence disturbs adipocyte autophagy and hinders adipocyte differentiation, survival, and function with differential effects on brown and white ATs. These abnormalities cause loss of white ATs, whitening followed by loss of brown ATs, and impaired "browning" of white ATs. Consequently, mice exhibit compromised thermogenic capacity and develop dyslipidemia, hepatic steatosis, insulin resistance, and type 2 diabetes. While these effects of PIK3C3 largely contrast previous findings with the autophagy-related (ATG) protein ATG7 in adipocytes, mice with a combined deficiency in both factors reveal a dominant role of the PIK3C3-deficient phenotype. We have also found that dietary lipid excess exacerbates AT pathologies caused by PIK3C3 deficiency. Surprisingly, glucose tolerance is spared in adipocyte-specific PIK3C3-deficient mice, a phenotype that is more evident during dietary lipid excess. These findings reveal a crucial yet complex role for PIK3C3 in ATs, with potential therapeutic implications.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Animales , Ratones , Fosfatidilinositol 3-Quinasas Clase III/genética , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Adipocitos/metabolismo , Lípidos , Tejido Adiposo Pardo/metabolismo , Adipocitos Marrones/metabolismoRESUMEN
BACKGROUND: Invariant natural killer T (iNKT) cells play protective or pathogenic roles in a variety of immune and inflammatory diseases. However, whether iNKT cells contribute to the progression of acute neuroinflammation remains unclear. Thus, we addressed this question with a mouse model of lipopolysaccharide (LPS)-induced acute neuroinflammation. METHODS: For induction of acute neuroinflammation, wild-type (WT) C57BL/6 (B6) mice were injected intraperitoneally (i.p.) with LPS for either three or five consecutive days, and then these mice were analyzed for brain-infiltrating leukocytes or mouse behaviors, respectively. To examine the role of iNKT cell activation in LPS-induced neuroinflammation, mice were injected i.p. with the iNKT cell agonist α-galactosylceramide (α-GalCer) seven days prior to LPS treatment. Immune cells infiltrated into the brain during LPS-induced neuroinflammation were determined by flow cytometry. In addition, LPS-induced clinical behavior symptoms such as depressive-like behavior and memory impairment in mice were evaluated by the open field and Y-maze tests, respectively. RESULTS: We found that iNKT cell-deficient Jα18 mutant mice display delayed disease progression and decreased leukocyte infiltration into the brain compared with WT mice, indicating that iNKT cells contribute to the pathogenesis of LPS-induced neuroinflammation. Since it has been reported that pre-treatment with α-GalCer, an iNKT cell agonist, can convert iNKT cells towards anti-inflammatory phenotypes, we next explored whether pre-activation of iNKT cells with α-GalCer can regulate LPS-induced neuroinflammation. Strikingly, we found that α-GalCer pre-treatment significantly delays the onset of clinical symptoms, including depression-like behavior and memory impairment, while decreasing brain infiltration of pro-inflammatory natural killer cells and neutrophils, in this model of LPS-induced neuroinflammation. Such anti-inflammatory effects of α-GalCer pre-treatment closely correlated with iNKT cell polarization towards IL4- and IL10-producing phenotypes. Furthermore, α-GalCer pre-treatment restored the expression of suppressive markers on brain regulatory T cells during LPS-induced neuroinflammation. CONCLUSION: Our findings provide strong evidence that α-GalCer-induced pre-activation of iNKT cells expands iNKT10 cells, mitigating depressive-like behaviors and brain infiltration of inflammatory immune cells induced by LPS-induced acute neuroinflammation. Thus, we suggest the prophylactic potential of iNKT cells and α-GalCer against acute neuroinflammation.
Asunto(s)
Encéfalo , Galactosilceramidas , Lipopolisacáridos , Ratones Endogámicos C57BL , Células T Asesinas Naturales , Enfermedades Neuroinflamatorias , Animales , Galactosilceramidas/farmacología , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/efectos de los fármacos , Encéfalo/patología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Masculino , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/inducido químicamente , Ratones , Citocinas/metabolismoRESUMEN
Lymphocytes can be functionally partitioned into subsets belonging to the innate or adaptive arms of the immune system. Subsets of innate and innate-like lymphocytes may or may not express Ag-specific receptors of the adaptive immune system, yet they are poised to respond with innate-like speed to pathogenic insults but lack the capacity to develop classical immunological memory. These lymphocyte subsets display a number of common properties that permit them to integrate danger and stress signals dispatched by innate sensor cells to facilitate the generation of specialized effector immune responses tailored toward specific pathogens or other insults. In this review, we discuss the functions of distinct subsets of innate and innate-like lymphocytes. A better understanding of the mechanisms by which these cells are activated in different contexts, their interactions with other immune cells, and their role in health and disease may inform the development of new or improved immunotherapies.
Asunto(s)
Inmunidad Innata , Linfocitos , Memoria Inmunológica , InmunoterapiaRESUMEN
The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αß(+) T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αß(+) memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αß(+) memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αß(+) memory T cells that form the first line of defense at the largest entry port for pathogens.
Asunto(s)
Células Dendríticas/metabolismo , Listeriosis/inmunología , Glicoproteínas de Membrana/metabolismo , Células Precursoras de Linfocitos T/metabolismo , Linfocitos T/metabolismo , Animales , Antígenos/inmunología , Antígenos/metabolismo , Antígenos CD8/metabolismo , Diferenciación Celular , Selección Clonal Mediada por Antígenos , Células Dendríticas/inmunología , Células Dendríticas/patología , Inmunidad Mucosa/genética , Memoria Inmunológica/genética , Activación de Linfocitos/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Precursoras de Linfocitos T/inmunología , Células Precursoras de Linfocitos T/patología , Linfocitos T/inmunología , Linfocitos T/patología , Transgenes/genéticaRESUMEN
Innate immune responses are critical for mucosal immunity. Here we describe an innate lymphocyte population, iCD8α cells, characterized by expression of CD8α homodimers. iCD8α cells exhibit innate functional characteristics such as the capacity to engulf and kill bacteria. Development of iCD8α cells depends on expression of interleukin-2 receptor γ chain (IL-2Rγc), IL-15, and the major histocompatibility complex (MHC) class Ib protein H2-T3, also known as the thymus leukemia antigen or TL. While lineage tracking experiments indicated that iCD8α cells have a lymphoid origin, their development was independent of the transcriptional suppressor Id2, suggesting that these cells do not belong to the family of innate lymphoid cells. Finally, we identified cells with a similar phenotype in humans, which were profoundly depleted in newborns with necrotizing enterocolitis. These findings suggest a critical role of iCD8α cells in immune responses associated with the intestinal epithelium.
Asunto(s)
Presentación de Antígeno/inmunología , Antígenos CD8/biosíntesis , Inmunidad Mucosa/inmunología , Mucosa Intestinal/citología , Linfocitos/inmunología , Animales , Citrobacter rodentium/inmunología , Citocalasina D/farmacología , Enterocolitis Necrotizante , Helicobacter pylori/inmunología , Antígenos de Histocompatibilidad Clase I/biosíntesis , Humanos , Proteína 2 Inhibidora de la Diferenciación/genética , Subunidad gamma Común de Receptores de Interleucina/biosíntesis , Interleucina-15/biosíntesis , Interleucina-2/biosíntesis , Interleucina-7/biosíntesis , Mucosa Intestinal/inmunología , Activación de Linfocitos/inmunología , Linfocitos/clasificación , Linfocitos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunologíaRESUMEN
Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77tg) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Vα14-Jα18 TCR-α chain gene into the Nur77tg (Nur77tg;Vα14tg) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-γ-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.
Asunto(s)
Diferenciación Celular , Tolerancia Inmunológica , Células T Asesinas Naturales , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Ratones , Ratones Noqueados , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/inmunología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Receptores de Antígenos de Linfocitos T , TimocitosRESUMEN
Interleukin-7 (IL-7) plays a vital role in the homeostasis of CD4+ and CD8+ T cells. Although IL-7 has been implicated in T helper (Th)1- and Th17-mediated autoinflammatory diseases, its role in Th2-type allergic disorders, such as atopic dermatitis (AD), remains unclear. Thus, to elucidate the effects of IL-7 deficiency on AD development, we generated IL-7-deficient AD-prone mice by backcrossing IL-7 knockout (KO) B6 mice onto the NC/Nga (NC) mouse strain, a model for human AD. As expected, IL-7 KO NC mice displayed defective development of conventional CD4+ and CD8+ T cells compared with wild type (WT) NC mice. However, IL-7 KO NC mice presented with enhanced AD clinical scores, IgE hyperproduction, and increased epidermal thickness compared with WT NC mice. Moreover, IL-7 deficiency decreased Th1, Th17, and IFN-γ-producing CD8+ T cells but increased Th2 cells in the spleen of NC mice, indicating that a reduced Th1/Th2 ratio correlates with severity of AD pathogenesis. Furthermore, significantly more basophils and mast cells infiltrated the skin lesions of IL-7 KO NC mice. Taken together, our findings suggest that IL-7 could be a useful therapeutic target for treating Th2-mediated skin inflammations, such as AD.
Asunto(s)
Dermatitis Atópica , Enfermedades de la Piel , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/patología , Citocinas , Dermatitis Atópica/tratamiento farmacológico , Modelos Animales de Enfermedad , Interleucina-7/genética , Interleucina-7/metabolismo , Piel/patología , Enfermedades de la Piel/patología , Células Th2RESUMEN
Beta-glucan (ß-glucan) is a natural polysaccharide produced by fungi, bacteria, and plants. Although it has been reported that ß-glucan enhances innate immune memory responses, it is unclear whether different types of ß-glucans display similar immune effects. To address this issue, we employed zymosan (ß-1,3-glycosidic linkage) and pustulan (ß-1,6-glycosidic linkage) to investigate their in vivo effects on innate memory immune responses. We examined the changes of innate memory-related markers in macrophages and natural killer (NK) cells, two immune cell types that display innate memory characteristics, at two different time points (16 h and 7 days) after ß-glucan stimulation. We found that short-term (16 h) zymosan treatment significantly induced macrophages to upregulate IL15 production and increased surface IL15Rα expression on NK cells. In addition, long-term (7 days) zymosan treatment significantly induced macrophages to upregulate the expression of innate memory-related markers (e.g., TNFα, HIF1α, and mTOR) and induced NK cells to express enhanced levels of KLRG1, known as an innate memory-like marker. Our results provide support that zymosan can be an effective adjuvant to promote innate memory immune responses, providing a bridge between innate and adaptive immune cells to enhance various immune responses such as those directed against tumors.
Asunto(s)
Interleucina-15 , beta-Glucanos , Ratones , Animales , Zimosan/farmacología , Macrófagos , beta-Glucanos/farmacología , Células Asesinas Naturales , Inmunidad InnataRESUMEN
Obesity is accompanied by and accelerated with chronic inflammation in adipose tissue, especially visceral adipose tissue (VAT). This low-level inflammation predisposes the host to the development of metabolic disease, most notably type 2 diabetes. We have focused on the capacity of glycolipid-reactive, CD1d-restricted natural killer T (NKT) cells to modulate obesity and its associated metabolic sequelae. We previously reported that CD1d knockout (KO) mice are partially protected against the development of obesity-associated insulin resistance, and these findings were recapitulated in mice with an adipocyte-specific CD1d deficiency, suggesting that NKT cell-adipocyte interactions play a critical role in exacerbating disease. However, many other CD1d-expressing cells contribute to the in vivo responses of NKT cells to lipid antigens. In the present study, we examined the role of CD1d expression by macrophages (MÏ) in the development of obesity-associated metabolic inflammation using LysMcre-cd1d1f/f mice where the CD1d1 gene is disrupted in a MÏ-specific manner. Unexpectedly, these animals contained a higher frequency of T-bet+ CD4+ T cells in VAT with increased production of Th1 cytokines that aggravated VAT inflammation. MÏ from mutant mice displayed increased production of IL-12p40, suggesting M1 polarization. These findings indicate that interactions of CD1d on MÏ with NKT cells play a beneficial role in obesity-associated VAT inflammation and insulin resistance with a sharp contrast to an aggravating role of CD1d in another type of antigen-presenting cell, dendritic cells.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Células T Asesinas Naturales , Tejido Adiposo/metabolismo , Animales , Antígenos CD1d , Inflamación/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/metabolismoRESUMEN
Tuberculosis (TB) is one of the deadliest diseases, claiming ~2 million deaths annually worldwide. The majority of people in TB endemic regions are vaccinated with Bacillus Calmette Guerin (BCG), which is the only usable vaccine available. BCG is efficacious against meningeal and disseminated TB in children, but protective responses are relatively short-lived and fail to protect against adult pulmonary TB. The longevity of vaccine efficacy critically depends on the magnitude of long-lasting central memory T (TCM) cells, a major source of which is stem cell-like memory T (TSM) cells. These TSM cells exhibit enhanced self-renewal capacity as well as to rapidly respond to antigen and generate protective poly-functional T cells producing IFN-γ, TNF-α, IL-2 and IL-17. It is now evident that T helper Th 1 and Th17 cells are essential for host protection against TB. Recent reports have indicated that Th17 cells preserve the molecular signature for TSM cells, which eventually differentiate into IFN-γ-producing effector cells. BCG is ineffective in inducing Th17 cell responses, which might explain its inadequate vaccine efficacy. Here, we show that revaccination with BCG along with clofazimine treatment promotes TSM differentiation, which continuously restores TCM and T effector memory (TEM) cells and drastically increases vaccine efficacy in BCG-primed animals. Analyses of these TSM cells revealed that they are predominantly precursors to host protective Th1 and Th17 cells. Taken together, these findings revealed that clofazimine treatment at the time of BCG revaccination provides superior host protection against TB by increasing long-lasting TSM cells.
Asunto(s)
Vacuna BCG/inmunología , Vacuna BCG/metabolismo , Clofazimina/farmacología , Memoria Inmunológica/inmunología , Animales , Vacuna BCG/farmacología , Clofazimina/metabolismo , Quimioterapia Combinada/métodos , Femenino , Inmunización Secundaria/métodos , Inmunogenicidad Vacunal/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/inmunología , Células Madre/inmunología , Células TH1/inmunología , Células Th17/inmunología , Tuberculosis/inmunología , Tuberculosis Pulmonar/inmunologíaRESUMEN
It is now appreciated that a group of lymphoid lineage cells, collectively called innate-like effector lymphocytes, have evolved to integrate information relayed by the innate sensory immune system about the state of the local tissue environment and to pass on this context to downstream effector innate and adaptive immune responses. Thereby, innate functions engrained into such innate-like lymphoid lineage cells during development can control the quality and magnitude of an immune response to a tissue-altering pathogen and facilitate the formation of memory engrams within the immune system. These goals are accomplished by the innate lymphoid cells that lack antigen-specific receptors, γδ T cell receptor (TCR)-expressing T cells, and several αß TCR-expressing T cell subsets-such as natural killer T cells, mucosal-associated invariant T cells, et cetera. Whilst we briefly consider the commonalities in the origins and functions of these diverse lymphoid subsets to provide context, the primary topic of this review is to discuss how the semi-invariant natural killer T cells got this way in evolution through lineage commitment and onward ontogeny. What emerges from this discourse is the question: Has a "limbic immune system" emerged (screaming quietly in plain sight!) out of what has been dubbed "in-betweeners"?
Asunto(s)
Células T Asesinas Naturales , Humanos , Inmunidad Innata , Células Asesinas Naturales , Receptores de Antígenos de Linfocitos T gamma-delta , Subgrupos de Linfocitos TRESUMEN
Acute myocardial infarction (MI) provokes an inflammatory response in the heart that removes damaged tissues to facilitate tissue repair/regeneration. However, overactive and prolonged inflammation compromises healing, which may be counteracted by antiinflammatory mechanisms. A key regulatory factor in an inflammatory response is the antiinflammatory cytokine IL-10, which can be produced by a number of immune cells, including subsets of B lymphocytes. Here, we investigated IL-10-producing B cells in pericardial adipose tissues (PATs) and their role in the healing process following acute MI in mice. We found that IL-10-producing B cells were enriched in PATs compared to other adipose depots throughout the body, with the majority of them bearing a surface phenotype consistent with CD5+ B-1a cells (CD5+ B cells). These cells were detected early in life, maintained a steady presence during adulthood, and resided in fat-associated lymphoid clusters. The cytokine IL-33 and the chemokine CXCL13 were preferentially expressed in PATs and contributed to the enrichment of IL-10-producing CD5+ B cells. Following acute MI, the pool of CD5+ B cells was expanded in PATs. These cells accumulated in the infarcted heart during the resolution of MI-induced inflammation. B cell-specific deletion of IL-10 worsened cardiac function, exacerbated myocardial injury, and delayed resolution of inflammation following acute MI. These results revealed enrichment of IL-10-producing B cells in PATs and a significant contribution of these cells to the antiinflammatory processes that terminate MI-induced inflammation. Together, these findings have identified IL-10-producing B cells as therapeutic targets to improve the outcome of MI.
Asunto(s)
Tejido Adiposo/metabolismo , Linfocitos B/inmunología , Interleucina-10/metabolismo , Infarto del Miocardio/inmunología , Pericardio/metabolismo , Tejido Adiposo/citología , Animales , Quimiocina CXCL13/metabolismo , Femenino , Inflamación/inmunología , Inflamación/patología , Interleucina-10/genética , Interleucina-33/metabolismo , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/patología , Pericardio/citología , Regeneración/fisiologíaRESUMEN
We have previously shown that a deficiency of CD1d-restricted invariant natural killer T (iNKT) cells exacerbates dextran sulfate sodium (DSS)-induced colitis in Yeti mice that exhibit IFNγ-mediated hyper-inflammation. Although iNKT cell-deficiency resulted in reduced Foxp3 expression by mesenteric lymph node (MLN) CD4+ T cells in DSS-treated Yeti mice, the cellular mechanisms that regulate Foxp3 expression by CD25+CD4+ T cells during intestinal inflammation remain unclear. We found that Foxp3-CD25+CD4+ T cells expressing Th1 and Th17 phenotypic hallmarks preferentially expanded in the MLNs of DSS-treated Yeti/CD1d knockout (KO) mice. Moreover, adoptive transfer of Yeti iNKT cells into iNKT cell-deficient Jα18 KO mice effectively suppressed the expansion of MLN Foxp3-CD25+CD4+ T cells during DSS-induced colitis. Interestingly, MLN dendritic cells (DCs) purified from DSS-treated Yeti/CD1d KO mice promoted the differentiation of naive CD4+ T cells into Foxp3-CD25+CD4+ T cells rather than regulatory T (Treg) cells, indicating that MLN DCs might mediate Foxp3+CD25+CD4+ T cell expansion in iNKT cell-sufficient Yeti mice. Furthermore, we showed that Foxp3-CD25+CD4+ T cells were pathogenic in DSS-treated Yeti/CD1d KO mice. Our result suggests that pro-inflammatory DCs and CD1d-restricted iNKT cells play opposing roles in Foxp3 expression by MLN CD25+CD4+ T cells during IFNγ-mediated intestinal inflammation, with potential therapeutic implications.
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Colitis , Células Dendríticas , Células T Asesinas Naturales , Animales , Ratones , Colitis/patología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Interferón gamma/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Células T Asesinas Naturales/metabolismo , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Linfocitos T CD4-Positivos/inmunología , Subunidad alfa del Receptor de Interleucina-2 , Células Dendríticas/inmunología , Células Dendríticas/metabolismoRESUMEN
Although 3-aminopropyl functionalized magnesium phyllosilicate nanoparticles (hereafter aminoclay nanoparticles, ACNs) are well-known nanomaterials employed as drug carriers, their effects on immune cells remain unclear. To address this issue, we explored murine dendritic cells (DCs) as these cells belong to the innate arm of the immune system and function as antigen-presenting cells to elicit adaptive immune responses. We examined the in vitro effects of ACNs on DCs isolated from B6 mice. ACN treatment significantly down-regulated the expression of inflammasome-related markers, including NLRP3, caspase-1, and IL1ß. The ACNs-induced anti-inflammatory DC phenotype was further confirmed by down-regulation of the AKT/mTOR/HIF1α signaling pathway. Such anti-inflammatory effects of ACNs on DCs occurred independently of DC subtypes. To document the effects of ACNs on DCs more clearly, we examined their anti-inflammatory effects on lipopolysaccharide (LPS)-activated DCs. As expected, excessive inflammatory responses (increased mitochondrial ROS and Th1-type cytokines such as IL12 and IL1ß) of LPS-activated DCs were dramatically attenuated by ACN treatment. Furthermore, ACNs down-regulated IFNγ production by antigen-specific CD4+ T cells, which is consistent with a reduced inflammatory phenotype of DCs. Overall, our results provide support for employing ACNs as drug delivery materials with therapeutic potential to control inflammatory disorders.
Asunto(s)
Lipopolisacáridos , Nanopartículas , Animales , Ratones , Lipopolisacáridos/farmacología , Citocinas/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/metabolismo , Inmunidad , Células DendríticasRESUMEN
Intestinal intraepithelial lymphocytes (IELs) are a large and diverse population of lymphoid cells that reside between the intestinal epithelial cells (IECs) that form the intestinal mucosal barrier. Although IEL biology has traditionally focused on T cells, recent studies have identified several subsets of T cell receptor (TCR)-negative IELs with intriguing properties. New insight into the development, homeostasis, and functions of distinct IEL subsets has recently been provided. Additional studies have revealed intricate interactions between different IEL subsets, reciprocal interactions between IELs and IECs, and communication of IELs with immune cells that reside outside the intestinal epithelium. We review here sentinel functions of IELs in the maintenance of the mucosal barrier integrity, as well as how dysregulated IEL responses can contribute to pathology.
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Inflamación/inmunología , Mucosa Intestinal/fisiología , Linfocitos Intraepiteliales/inmunología , Animales , Comunicación Celular , Diferenciación Celular , Homeostasis , Humanos , Inmunidad MucosaRESUMEN
We have previously shown that CD1d-restricted iNKT cells suppress dysregulated IFNγ expression and intestinal inflammation in Yeti mice on the C57BL/6 background. Since type 3 innate lymphoid cells (ILC3s) in mesenteric lymph nodes (MLN) protect against intestinal inflammation in a CD1d-associated manner, we investigated whether crosstalk between iNKT cells and MLN ILC3s controls IFNγ-mediated intestinal inflammation in Yeti mice. We found that Yeti mice display increased levels of ILC3s and that iNKT cell deficiency in Yeti/CD1d KO mice decreases levels of IL22-producing ILC3s during DSS-induced colitis. This finding indicates that iNKT cells and ILC3s cooperate to regulate intestinal inflammation in Yeti mice. Yeti iNKT cells displayed a pronounced anti-inflammatory (IL4- or IL9-producing) phenotype during colitis. Their adoptive transfer to iNKT cell-deficient animals induced a significant increase in IL22 production by ILC3s, indicating that crosstalk between iNKT cells and ILC3s plays a critical role in modulating colitis in Yeti mice. Moreover, we showed that the IL9-producing subset of iNKT cells potently enhances IL22-producing ILC3s in vivo. Taken together, our results identify a central role of the iNKT cell-ILC3 axis in ameliorating IFNγ-mediated intestinal inflammation.
Asunto(s)
Antígenos CD1d/genética , Inflamación/genética , Interferón gamma/genética , Interleucinas/genética , Linfocitos/metabolismo , Animales , Colitis/inducido químicamente , Colitis/genética , Colitis/inmunología , Sulfato de Dextran/toxicidad , Humanos , Inmunidad Innata/genética , Inflamación/inmunología , Inflamación/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Intestinos/patología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Ratones , Ratones Noqueados , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/patología , Circulación Esplácnica/genética , Interleucina-22RESUMEN
The SWItch (SWI)3-related gene (SRG3) product, a SWI/Sucrose Non-Fermenting (SNF) chromatin remodeling subunit, plays a critical role in regulating immune responses. We have previously shown that ubiquitous SRG3 overexpression attenuates the progression of Th1/Th17-mediated experimental autoimmune encephalomyelitis. However, it is unclear whether SRG3 overexpression can affect the pathogenesis of inflammatory skin diseases such as atopic dermatitis (AD), a Th2-type immune disorder. Thus, to elucidate the effects of SRG3 overexpression in AD development, we bred NC/Nga (NC) mice with transgenic mice where SRG3 expression is driven by the ß-actin promoter (SRG3ß-actin mice). We found that SRG3ß-actin NC mice exhibit increased AD development (e.g., a higher clinical score, immunoglobulin E (IgE) hyperproduction, and an increased number of infiltrated mast cells and basophils in skin lesions) compared with wild-type NC mice. Moreover, the severity of AD pathogenesis in SRG3ß-actin NC mice correlated with expansion of interleukin 4 (IL4)-producing basophils and mast cells, and M2 macrophages. Furthermore, this accelerated AD development is strongly associated with Treg cell suppression. Collectively, our results have identified that modulation of SRG3 function can be applied as one of the options to control AD pathogenesis.
Asunto(s)
Ensamble y Desensamble de Cromatina , Dermatitis Atópica/etiología , Expresión Génica , Células Th2/inmunología , Células Th2/metabolismo , Factores de Transcripción/genética , Actinas/metabolismo , Animales , Biopsia , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Inmunidad Celular , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Transgénicos , Índice de Severidad de la EnfermedadRESUMEN
We previously showed that ubiquitous overexpression of the chromatin remodeling factor SWItch3-related gene (SRG3) promotes M2 macrophage differentiation, resulting in anti-inflammatory responses in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Since hepatic macrophages are responsible for sepsis-induced liver injury, we investigated herein the capacity of transgenic SRG3 overexpression (SRG3ß-actin mice) to modulate sepsis in mice exposed to lipopolysaccharide (LPS) plus d-galactosamine (d-GalN). Our results demonstrated that ubiquitous SRG3 overexpression significantly protects mice from LPS/d-GalN-induced lethality mediated by hepatic M1 macrophages. These protective effects of SRG3 overexpression correlated with the phenotypic conversion of hepatic macrophages from an M1 toward an M2 phenotype. Furthermore, SRG3ß-actin mice had decreased numbers and activation of natural killer (NK) cells but not natural killer T (NKT) cells in the liver during sepsis, indicating that SRG3 overexpression might contribute to cross-talk between NK cells and macrophages in the liver. Finally, we demonstrated that NKT cell-deficient CD1d KO/SRG3ß-actin mice are protected from LPS/d-GalN-induced sepsis, indicating that NKT cells are dispensable for SRG3-mediated sepsis suppression. Taken together, our findings provide strong evidence that SRG3 overexpression may serve as a therapeutic approach to control overwhelming inflammatory diseases such as sepsis.
Asunto(s)
Cromatina/metabolismo , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Hígado/patología , Macrófagos/metabolismo , Células T Asesinas Naturales/metabolismo , Sepsis/inducido químicamente , Sepsis/prevención & control , Factores de Transcripción/metabolismo , Actinas/genética , Animales , Ensamble y Desensamble de Cromatina , Células Dendríticas/metabolismo , Galactosamina , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Sustancias Protectoras/metabolismo , Sepsis/inmunología , Sepsis/patología , Índice de Severidad de la EnfermedadRESUMEN
The intestine is continuously exposed to commensal microorganisms, food, and environmental agents and also serves as a major portal of entry for many pathogens. A critical defense mechanism against microbial invasion in the intestine is the single layer of epithelial cells that separates the gut lumen from the underlying tissues. The barrier function of the intestinal epithelium is supported by cells and soluble factors of the intestinal immune system. Chief among them are intestinal intraepithelial lymphocytes (iIELs), which are embedded in the intestinal epithelium and represent one of the single largest populations of lymphocytes in the body. Compared with lymphocytes in other parts of the body, iIELs exhibit unique phenotypic, developmental, and functional properties that reflect their key roles in maintaining the intestinal epithelial barrier. In this article, we review the biology of iIELs in supporting normal health and how their dysregulation can contribute to disease.