RESUMEN
Although mice normally enter labor when their ovaries stop producing progesterone (luteolysis), parturition can also be triggered in this species through uterus-intrinsic pathways potentially analogous to the ones that trigger parturition in humans. Such pathways, however, remain largely undefined in both species. Here, we report that mice deficient in innate type 2 immunity experienced profound parturition delays when manipulated endocrinologically to circumvent luteolysis, thus obliging them to enter labor through uterus-intrinsic pathways. We found that these pathways were in part driven by the alarmin IL-33 produced by uterine interstitial fibroblasts. We also implicated important roles for uterine group 2 innate lymphoid cells, which demonstrated IL-33-dependent activation prior to labor onset, and eosinophils, which displayed evidence of elevated turnover in the prepartum uterus. These findings reveal a role for innate type 2 immunity in controlling the timing of labor onset through a cascade potentially relevant to human parturition.
Asunto(s)
Interleucina-33 , Luteólisis , Embarazo , Femenino , Ratones , Animales , Humanos , Interleucina-33/metabolismo , Inmunidad Innata , Miometrio/metabolismo , Linfocitos , Parto/metabolismoRESUMEN
During the first trimester of pregnancy the uterus is massively infiltrated by decidual natural killer cells (dNK). These cells are not killers, but they rather provide a microenvironment that is propitious to healthy placentation. Human cytomegalovirus (HCMV) is the most common cause of intrauterine viral infections and a known cause of severe birth defects or fetal death. The rate of HCMV congenital infection is often low in the first trimester of pregnancy. The mechanisms controlling HCMV spreading during pregnancy are not yet fully revealed, but evidence indicating that the innate immune system plays a role in controlling HCMV infection in healthy adults exists. In this study, we investigated whether dNK cells could be involved in controlling viral spreading and in protecting the fetus against congenital HCMV infection. We found that freshly isolated dNK cells acquire major functional and phenotypic changes when they are exposed to HCMV-infected decidual autologous fibroblasts. Functional studies revealed that dNK cells, which are mainly cytokines and chemokines producers during normal pregnancy, become cytotoxic effectors upon their exposure to HCMV-infected autologous decidual fibroblasts. Both the NKG2D and the CD94/NKG2C or 2E activating receptors are involved in the acquired cytotoxic function. Moreover, we demonstrate that CD56(pos) dNK cells are able to infiltrate HCMV-infected trophoblast organ culture ex-vivo and to co-localize with infected cells in situ in HCMV-infected placenta. Taken together, our results present the first evidence suggesting the involvement of dNK cells in controlling HCMV intrauterine infection and provide insights into the mechanisms through which these cells may operate to limit the spreading of viral infection to fetal tissues.
Asunto(s)
Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Decidua/inmunología , Células Asesinas Naturales/inmunología , Antígeno CD56/metabolismo , Línea Celular , Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/metabolismo , Decidua/citología , Decidua/virología , Proteína Ligando Fas/metabolismo , Femenino , Células HEK293 , Humanos , Células Asesinas Naturales/metabolismo , Subfamília C de Receptores Similares a Lectina de Células NK/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Subfamília D de Receptores Similares a Lectina de las Células NK/inmunología , Subfamília D de Receptores Similares a Lectina de las Células NK/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Placentación , Embarazo , Primer Trimestre del Embarazo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , ÚteroRESUMEN
Early phases of human pregnancy are associated with the accumulation of a unique subset of natural killer (NK) cells in the maternal decidua. Decidual NK (dNK) cells that are devoid of cytotoxicity play a pivotal role in successful pregnancy. By secreting large amounts of cytokines/chemokines and angiogenic factors, dNK cells participate in all steps of placentation including trophoblast invasion into the maternal endometrium and vascular remodelling. In this review, we summarize some of dNK cell features and discuss more recent exciting data that challenge the conventional view of these cells. Our new data demonstrate that dNK cells undergo fine tuning or even subvert their classical inhibitory machinery and turn into a real defence force in order to prevent the spread of viruses to fetal tissue. Today it is not clear how these phenotypic and functional adaptations impact cellular cross-talk at the fetal-maternal interface and tissue homeostasis. Ultimately, precise understanding of the molecular mechanisms that govern dNK cell plasticity during congenital human cytomegalovirus infection should lead to the design of more robust strategies to reverse immune escape during viral infection and cancer.
Asunto(s)
Decidua/inmunología , Células Asesinas Naturales/inmunología , Subgrupos Linfocitarios/inmunología , Placentación , Animales , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/transmisión , Infecciones por Citomegalovirus/virología , Decidua/metabolismo , Femenino , Humanos , Tolerancia Inmunológica , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Células Asesinas Naturales/metabolismo , Subgrupos Linfocitarios/metabolismo , Intercambio Materno-Fetal , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/prevención & control , Complicaciones Infecciosas del Embarazo/virologíaRESUMEN
Aging is characterized by gradual immune dysfunction and increased disease risk. Genomic instability is considered central to the aging process, but the underlying mechanisms of DNA damage are insufficiently defined. Cells in confined environments experience forces applied to their nucleus, leading to transient nuclear envelope rupture (NER) and DNA damage. Here, we show that Lamin A/C protects lung alveolar macrophages (AMs) from NER and hallmarks of aging. AMs move within constricted spaces in the lung. Immune-specific ablation of lamin A/C results in selective depletion of AMs and heightened susceptibility to influenza virus-induced pathogenesis and lung cancer growth. Lamin A/C-deficient AMs that persist display constitutive NER marks, DNA damage and p53-dependent senescence. AMs from aged wild-type and from lamin A/C-deficient mice share a lysosomal signature comprising CD63. CD63 is required to limit damaged DNA in macrophages. We propose that NER-induced genomic instability represents a mechanism of aging in AMs.
Asunto(s)
Lamina Tipo A , Macrófagos Alveolares , Animales , Ratones , Lamina Tipo A/genética , Membrana Nuclear , Pulmón , Envejecimiento/genética , Inestabilidad GenómicaRESUMEN
A little-appreciated feature of early pregnancy is that embryo implantation and placental outgrowth do not evoke wound-healing responses in the decidua, the specialized endometrial tissue that surrounds the conceptus. Here, we provide evidence that this phenomenon is partly due to an active program of gene silencing mediated by EZH2, a histone methyltransferase that generates repressive histone 3 lysine 27 trimethyl (H3K27me3) histone marks. We find that pregnancies in mice with EZH2-deficient decidual stromal cells frequently fail by mid-gestation, with the decidua showing ectopic myofibroblast formation, peri-embryonic collagen deposition, and gene expression profiles associated with transforming growth factor ß (TGF-ß)-driven fibroblast activation and fibrogenic extracellular matrix (ECM) remodeling. Analogous responses are observed when the mutant decidua is surgically wounded, while blockade of TGF-ß receptor signaling inhibits the defects and improves reproductive outcomes. Together, these results highlight a critical feature of reproductive success and have implications for the context-specific control of TGF-ß-mediated wound-healing responses elsewhere in the body.
Asunto(s)
Implantación del Embrión/fisiología , Silenciador del Gen/fisiología , Placenta/metabolismo , Factor de Crecimiento Transformador beta/genética , Cicatrización de Heridas/fisiología , Animales , Decidua/metabolismo , Embrión de Mamíferos/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Expresión Génica/fisiología , Histonas/metabolismo , Humanos , Ratones Endogámicos C57BL , Embarazo , Células del Estroma/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Uncovering the causes of pregnancy complications such as preterm labor requires greater insight into how the uterus remains in a noncontractile state until term and then surmounts this state to enter labor. Here, we show that dynamic generation and erasure of the repressive histone modification tri-methyl histone H3 lysine 27 (H3K27me3) in decidual stromal cells dictate both elements of pregnancy success in mice. In early gestation, H3K27me3-induced transcriptional silencing of select gene targets ensured uterine quiescence by preventing the decidua from expressing parturition-inducing hormone receptors, manifesting type 1 immunity, and most unexpectedly, generating myofibroblasts and associated wound-healing responses. In late gestation, genome-wide H3K27 demethylation allowed for target gene upregulation, decidual activation, and labor entry. Pharmacological inhibition of H3K27 demethylation in late gestation not only prevented term parturition, but also inhibited delivery while maintaining pup viability in a noninflammatory model of preterm parturition. Immunofluorescence analysis of human specimens suggested that similar regulatory events might occur in the human decidua. Together, these results reveal the centrality of regulated gene silencing in the uterine adaptation to pregnancy and suggest new areas in the study and treatment of pregnancy disorders.
Asunto(s)
Decidua/metabolismo , Histonas/metabolismo , Parto/metabolismo , Embarazo/metabolismo , Procesamiento Proteico-Postraduccional , Animales , Femenino , Silenciador del Gen/fisiología , Humanos , Masculino , Metilación , Ratones , Regulación hacia Arriba/fisiologíaRESUMEN
Hepatitis E virus (HEV) infection, particularly HEV genotype 1 (HEV-1), can result in fulminant hepatic failure and severe placental diseases, but mechanisms underlying genotype-specific pathogenicity are unclear and appropriate models are lacking. Here, we model HEV-1 infection ex vivo at the maternal-fetal interface using the decidua basalis and fetal placenta, and compare its effects to the less-pathogenic genotype 3 (HEV-3). We demonstrate that HEV-1 replicates more efficiently than HEV-3 both in tissue explants and stromal cells, produces more infectious progeny virions and causes severe tissue alterations. HEV-1 infection dysregulates the secretion of several soluble factors. These alterations to the cytokine microenvironment correlate with viral load and contribute to the tissue damage. Collectively, this study characterizes an ex vivo model for HEV infection and provides insights into HEV-1 pathogenesis during pregnancy that are linked to high viral replication, alteration of the local secretome and induction of tissue injuries.
Asunto(s)
Virus de la Hepatitis E/genética , Virus de la Hepatitis E/patogenicidad , Intercambio Materno-Fetal/fisiología , Células Cultivadas , Decidua/patología , Decidua/virología , Femenino , Genotipo , Humanos , Interferones/metabolismo , Embarazo , Células del Estroma/metabolismo , Replicación Viral , Interferón lambdaRESUMEN
The natural cytotoxicity receptors NKp46/NCR1, NKp44/NCR2 and NKp30/NCR3 are critical for natural killer (NK) cell functions. Their genes are transcribed into several splice variants whose physiological relevance is not yet fully understood. Here we report that decidua basalis NK (dNK) cells of the pregnant uterine mucosa and peripheral blood NK (pNK) cells, two functionally distinct subsets of the physiological NK cell pool, display differential expression of NKp30/NCR3 and NKp44/NCR2 splice variants. The presence of cytokines that are enriched within the decidual microenvironment is sufficient to convert the splice variant profile of pNK cells into one similar to that of dNK cells. This switch is associated with decreased cytotoxic function and major adaptations to the secretome, hallmarks of the decidual phenotype. Thus, NKp30/NCR3 and NKp44/NCR2 splice variants delineate functionally distinct NK cell subsets. To our knowledge, this is the first conclusive evidence underlining the physiological importance of NCR splice variants.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Células Asesinas Naturales/clasificación , Isoformas de Proteínas/metabolismo , Receptores Gatillantes de la Citotoxidad Natural/metabolismo , Adolescente , Adulto , Citocinas/genética , Citocinas/metabolismo , Decidua/citología , Femenino , Humanos , Células Asesinas Naturales/fisiología , Embarazo , Isoformas de Proteínas/genética , Receptores Gatillantes de la Citotoxidad Natural/genética , Adulto JovenRESUMEN
Tumor-produced extracellular matrix (ECM) proteins can be key elements in tumor growth and metastasis. Transforming growth factor beta-inducible (TGFBI) protein is a secreted ECM component that can have dual function in cancer, acting as tumor suppressor or promoter. Although TGFBI is expressed in human melanoma cells, the exact role it might have in melanoma metastasis remains elusive. Assessing the expression and secretion of TGFBI, we show that human metastatic melanomas express and secrete significantly higher amounts of TGFBI, compared with nevus lesions and primary melanoma tumors. Intravenous injection of highly metastatic human melanoma cells expressing shRNA that targets TGFBI assigns a critical role for TGFBI in the formation of melanoma distal metastases in nude mice. In vivo assays demonstrate that TGFBI silencing does not interfere with melanoma cells' dissemination to distal sites but rather with their proliferation and outgrowth within new microenvironment. In line, TGFBI silencing increases melanoma cells motility/invasion/extravasation in vitro but interferes with their progression through the cell cycle, drastically reducing their proliferation. Furthermore, we show that TGFBI is a regulator of cyclins and cyclin-dependent kinases in melanoma. Collectively, our data describe a mechanism of melanoma metastatic outgrowth via promotion of growth/survival by the ECM protein TGFBI.
Asunto(s)
Proteínas de la Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Melanoma/metabolismo , Neoplasias Cutáneas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Apoptosis , Biopsia , Adhesión Celular , Ciclo Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Femenino , Perfilación de la Expresión Génica , Silenciador del Gen , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Trasplante de Neoplasias , ARN Interferente Pequeño/metabolismoRESUMEN
AIMS: Allogeneic human cardiac-derived stem/progenitor cells (hCPC) are promising candidates for cardiac repair. They interact with T cells, major effectors of the adaptive immune response, inducing 'paracrine' anti-inflammatory effects that could sustain tissue repair/regeneration. Natural killer (NK) cells are major effectors of the innate immune system that might influence the persistence of therapeutic stem/progenitor cells. Therefore, to get through successful clinical translation and anticipate allogeneic hCPC persistence, we defined their crosstalk with NK cells under steady state and inflammatory conditions. METHODS AND RESULTS: By using an experimental model of allogeneic hCPC/NK cell interaction, we demonstrate that hCPC moderately trigger cytokine-activated, but not resting, NK cell killing that occurs through formation of lytic immunological synapse and NK cell natural cytotoxicity. Yet, inflammatory context substantially decreases their capacity to set cytokine-activated NK cell functions towards NK cell-cytotoxicity and protects hCPC from NK cell killing. Allogeneic hCPC also restrain NK cell-cytotoxicity against conventional targets and inflammatory cytokine secretion biasing the latter towards anti-inflammatory cytokines. Thus, hCPC are unprivileged targets for allogeneic NK cells and can restrain NK cell functions in allogeneic setting. CONCLUSION: Collectively, our data suggest that allogeneic hCPC/innate NK cells crosstalk within injured inflamed myocardium would permit their retention and might contribute to attenuating inflammation and to preventing adverse cardiac remodelling.
Asunto(s)
Comunicación Celular , Inflamación/metabolismo , Células Asesinas Naturales/metabolismo , Miocitos Cardíacos/metabolismo , Células Madre/metabolismo , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Citocinas/inmunología , Citocinas/metabolismo , Citotoxicidad Inmunológica , Humanos , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Miocitos Cardíacos/inmunología , Miocitos Cardíacos/patología , Fenotipo , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Transducción de Señal , Células Madre/inmunologíaRESUMEN
NK cells present in the peripheral blood respond rapidly to pathogens or pathogen-infected cells by various means including cytotoxicity and production of cytokines. Whether decidual NK (dNK) cells are able to play a similar role when the pregnant uterus is infected by viruses is still largely unknown. Decidual NK cells are generally considered as poorly cytotoxic when compared to their peripheral blood counterparts. However, we have recently demonstrated that freshly isolated dNK cells from healthy early pregnant uterus do have a cytotoxic potential mediated by the specific engagement of NKp46 activating receptor. We further found that the co-engagement of CD94/NKG2A inhibiting receptor drastically inhibits the cytolytic function of dNK. This latter observation suggests that in situ the CD94/NKG2A receptor interaction with its HLA-E specific ligand is a dominant negative regulatory mechanism that prevents unwanted dNK cell cytotoxicity in non-infected pregnant uterus. How do dNK cells behave when they are activated by virus-infected cells present at the maternal-fetal interface? Largely based on data obtained from circulating NK cells, this review briefly discusses the following questions: Does uterine viral infection promote decidual NK cell proliferative capacity in situ? Are dNK cells able to kill virus-infected autologous decidual target cells and thus limit the virus spreading to the fetus? Which viral-mediated signal(s) and molecular interactions may subvert inhibition of dNK cytotoxic potential? Does uterine viral infection promote decidual NK cell secretion of cytokines and chemokines that boost the anti-viral immune response?
Asunto(s)
Citotoxicidad Inmunológica , Decidua/inmunología , Células Asesinas Naturales/inmunología , Complicaciones Infecciosas del Embarazo/inmunología , Virosis/inmunología , Animales , Presentación de Antígeno , Antígenos Virales/inmunología , Circulación Sanguínea , Decidua/virología , Femenino , Humanos , Evasión Inmune , Activación de Linfocitos , Circulación Placentaria , EmbarazoRESUMEN
Here we discuss CD160 an essential NK cell activating receptor that remains poorly understood. CD160 receptor exhibits a number of unique structural and functional characteristics that are not common to other killer immunoglobulin-like receptors that recognize major histocompatibility complex (MHC) class I molecules: (1) In addition to humans and mice, the cd160 gene is conserved in several other mammal species; (2) cd160 is located outside the NK gene complex and the Leukocyte Receptor Complex in humans; (3) CD160 expression is associated to the CD56(dim) CD16+ cytotoxic NK cell phenotype; (4) both human and mouse CD160 recognize MHC class Ia and Ib molecules; (5) unlike the other MHC class I-dependent activating NK receptors, CD160 is a glycosylphosphatidylinositol-anchored molecule with a single immunoglobulin-like domain, and does not bear immunoreceptor tyrosine-based activation motifs. Consequently, CD160 cannot signal by itself, requiring the recruitment of adaptor proteins. CD160 recruits phosphoinositide-3 kinase to trigger cytotoxicity and cytokine secretion; (6) specific engagement of NK CD160 receptor expressed by circulating NK cells produces proinflammatory cytokines IFN-γ, TNF-α, and, most notably, IL-6 and IL-8 as well as MIP1-ß chemokine. The level of CD160-mediated IFN-γ production is always higher than the one observed after engagement of the CD16 receptor.