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The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use longitudinal two-photon imaging in awake mice and single-cell transcriptomics to elucidate the mechanisms of ChP regulation of brain inflammation. We used intracerebroventricular injections of lipopolysaccharides (LPS) to model meningitis in mice and observed that neutrophils and monocytes accumulated in the ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process and revealed that ChP epithelial cells transiently specialize to nurture immune cells, coordinating their recruitment, survival, and differentiation as well as regulation of the tight junctions that control the permeability of the ChP brain barrier. Collectively, we provide a mechanistic understanding and a comprehensive roadmap of neuroinflammation at the ChP brain barrier.
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Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process.
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Interleucina-17 , Microbiota , Regeneración Nerviosa , Células Th17 , Axones , Regeneración Nerviosa/fisiología , Células Receptoras Sensoriales , Animales , Ratones , Células Th17/citologíaRESUMEN
Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.
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Péptido Hidrolasas , Prurito , Receptor PAR-1 , Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Humanos , Ratones , Péptido Hidrolasas/metabolismo , Prurito/microbiología , Receptor PAR-1/metabolismo , Staphylococcus aureus/enzimología , Staphylococcus aureus/patogenicidad , Staphylococcus aureus/fisiología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patologíaRESUMEN
Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.
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Colitis , Células Caliciformes , Ratones , Humanos , Animales , Células Caliciformes/metabolismo , Nociceptores/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Colitis/metabolismo , Moco/metabolismo , Proteína 1 Modificadora de la Actividad de Receptores/metabolismoRESUMEN
The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense. Apparently paradoxical or conflicting reports in the literature also highlight the complexity of neuroimmune interactions that may depend on tissue- and microbe-specific cues. These findings expand our understanding of the nuanced mechanisms and the greater context of sensory neurons in innate immunity.
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Inmunidad Innata , Células Receptoras Sensoriales , Inmunidad Innata/fisiología , Neuroinmunomodulación/fisiología , HomeostasisRESUMEN
The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year3-5. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+ nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.
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Encéfalo , Meninges , Meningitis Bacterianas , Neuroinmunomodulación , Humanos , Encéfalo/inmunología , Encéfalo/microbiología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Meninges/inmunología , Meninges/microbiología , Meninges/fisiopatología , Dolor/etiología , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Meningitis Bacterianas/complicaciones , Meningitis Bacterianas/inmunología , Meningitis Bacterianas/microbiología , Meningitis Bacterianas/patología , Streptococcus agalactiae/inmunología , Streptococcus agalactiae/patogenicidad , Streptococcus pneumoniae/inmunología , Streptococcus pneumoniae/patogenicidad , Nociceptores/metabolismo , Proteína 1 Modificadora de la Actividad de Receptores/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismoRESUMEN
Streptococcus agalactiae, also known as group B Streptococcus (GBS), is the major cause of neonatal sepsis in humans. A critical step to infection is adhesion of bacteria to epithelial surfaces. GBS adhesins have been identified to bind extracellular matrix components and cellular receptors. However, several putative adhesins have no host binding partner characterised. We report here that surface-expressed ß protein of GBS binds to human CEACAM1 and CEACAM5 receptors. A crystal structure of the complex showed that an IgSF domain in ß represents a novel Ig-fold subtype called IgI3, in which unique features allow binding to CEACAM1. Bioinformatic assessment revealed that this newly identified IgI3 fold is not exclusively present in GBS but is predicted to be present in adhesins from other clinically important human pathogens. In agreement with this prediction, we found that CEACAM1 binds to an IgI3 domain found in an adhesin from a different streptococcal species. Overall, our results indicate that the IgI3 fold could provide a broadly applied mechanism for bacteria to target CEACAMs.
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Adhesinas Bacterianas/química , Antígenos CD/química , Antígeno Carcinoembrionario/química , Moléculas de Adhesión Celular/química , Adhesinas Bacterianas/metabolismo , Animales , Antígenos CD/metabolismo , Sitios de Unión , Células CHO , Antígeno Carcinoembrionario/metabolismo , Moléculas de Adhesión Celular/metabolismo , Cricetinae , Cricetulus , Proteínas Ligadas a GPI/química , Proteínas Ligadas a GPI/metabolismo , Células HeLa , Humanos , Unión Proteica , Streptococcus agalactiae/metabolismoRESUMEN
BACKGROUND: Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis. OBJECTIVE: We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation. METHODS: Wild-type mice, mice with selective and inducible depletion of basophils, and mice expressing Il4-driven enhanced green fluorescent protein were subjected to epicutaneous sensitization with ovalbumin or saline. Sensitized skin was examined by histology for epidermal thickening. Cells were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was evaluated by real-time reverse transcription-quantitative PCR. RESULTS: Basophils were important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, mast cells, and eosinophils in ovalbumin-sensitized mouse skin and for the local and systemic TH2 response to epicutaneous sensitization. Moreover, basophils were the major source of IL-4 in epicutaneous-sensitized mouse skin and promote the ability of dendritic cells to drive TH2 polarization of naive T cells. CONCLUSION: Basophils play an important role in the development of allergic skin inflammation induced by cutaneous exposure to antigen in mice.
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Basófilos , Dermatitis Atópica , Interleucina-4 , Ovalbúmina , Células Th2 , Animales , Basófilos/inmunología , Ratones , Interleucina-4/inmunología , Interleucina-4/genética , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Ovalbúmina/inmunología , Células Th2/inmunología , Piel/inmunología , Piel/patología , Ratones Endogámicos C57BL , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad , Células Dendríticas/inmunología , Ratones Transgénicos , Mastocitos/inmunologíaRESUMEN
OBJECTIVE: This population-based study explored emergency room visits (ERVs) from all-causes, circulatory and respiratory diseases among different occupational groups in Taiwan associated with ambient average temperature. METHOD: Daily area-age-sex specific ERVs records were obtained from the Taiwan's Ministry of Health and Welfare from 2009 to 2018. Distributed lag-nonlinear model (DLNM) was used to estimate the exposure-response relationships between daily average temperature and ERVs for all-causes, circulatory and respiratory diseases by occupational groups. Random-effects meta-analysis was used to pool the overall cumulative relative risk (RR) and 95% confidence interval (CI). RESULTS: The exposure-response curves showed ERVs of all-cause and respiratory diseases increased with rising temperature across all occupational groups. These effects were consistently stronger among younger (20-64 years old) and outdoor workers. In contrast, ERVs risk from circulatory diseases increased significantly during cold snaps, with a substantially higher risk for female workers. Interestingly, female workers, regardless of indoor or outdoor work, consistently showed a higher risk of respiratory ERVs during hot weather compared to males. Younger workers (20-64 years old) exhibited a higher risk of ERVs, likely due to job profiles with greater exposure to extreme temperatures. Notably, the highest risk of all-causes ERVs was observed in outdoor male laborers (union members), followed by farmers and private employees, with the lowest risk among indoor workers. Conversely, female indoor workers and female farmers faced the highest risk of respiratory ERVs. Again, female farmers with consistent outdoor exposure had the highest risk of circulatory ERVs during cold conditions. CONCLUSION: Our findings highlighted the complexity of temperature-related health risks associated with different occupational contexts. The population-level insights into vulnerable occupational groups could provide valuable comprehension for policymakers and healthcare practitioners.
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Mini-LED backlights energized by quantum-dot color conversion (QDCC) hold great potential for technological breakthroughs of liquid crystal displays. However, luminance uniformity issues should still be urgently solved owing to the large interval of direct-lit mini-LEDs, especially when covering with a QDCC film (QDCCF) with uniform thickness. Herein, we propose a uniformity improvement approach of mini-LED backlights by employing a QDCCF with nonuniform thickness based on the Lambertian distribution of mini-LEDs, which is demonstrated by screen-printing preparation and ray-tracing simulation. Experimental results show that the luminance uniformity of the nonuniform QDCCF can reach 89.91%, which is 24.92% higher than the uniform one. Ray-tracing simulation further elaborates the mechanism of this significant improvement. Finally, by employing this nonuniform QDCCF, a mini-LED backlight prototype is assembled and achieves high uniformity of 92.15%, good white balance with color coordinates of (0.3482, 0.3137), and high color gamut of 109% NTSC. This work should shed some new light on mini-LED-based display technology.
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Streptococcus agalactiae (Group B Streptococcus, GBS) normally colonizes healthy adults but can cause invasive disease, such as meningitis, in the newborn. To gain access to the central nervous system, GBS must interact with and penetrate brain or meningeal blood vessels; however, the exact mechanisms are still being elucidated. Here, we investigate the contribution of BspC, an antigen I/II family adhesin, to the pathogenesis of GBS meningitis. Disruption of the bspC gene reduced GBS adherence to human cerebral microvascular endothelial cells (hCMEC), while heterologous expression of BspC in non-adherent Lactococcus lactis conferred bacterial attachment. In a murine model of hematogenous meningitis, mice infected with ΔbspC mutants exhibited lower mortality as well as decreased brain bacterial counts and inflammatory infiltrate compared to mice infected with WT GBS strains. Further, BspC was both necessary and sufficient to induce neutrophil chemokine expression. We determined that BspC interacts with the host cytoskeleton component vimentin and confirmed this interaction using a bacterial two-hybrid assay, microscale thermophoresis, immunofluorescent staining, and imaging flow cytometry. Vimentin null mice were protected from WT GBS infection and also exhibited less inflammatory cytokine production in brain tissue. These results suggest that BspC and the vimentin interaction is critical for the pathogenesis of GBS meningitis.
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Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/metabolismo , Encéfalo/metabolismo , Meningitis Bacterianas/metabolismo , Infecciones Estreptocócicas/metabolismo , Streptococcus agalactiae/metabolismo , Vimentina/metabolismo , Animales , Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Encéfalo/irrigación sanguínea , Encéfalo/microbiología , Encéfalo/patología , Endotelio Vascular , Células HeLa , Humanos , Masculino , Meningitis Bacterianas/genética , Meningitis Bacterianas/patología , Ratones , Ratones Mutantes , Ovinos , Infecciones Estreptocócicas/genética , Infecciones Estreptocócicas/patología , Streptococcus agalactiae/genética , Streptococcus agalactiae/patogenicidad , Vimentina/genéticaRESUMEN
BACKGROUND: Osteosarcoma is the most common primary bone tumor in children and adolescents. However, some patients with osteosarcoma develop resistance to chemotherapy, leading to a poor clinical prognosis. Hence, effective therapeutic agents that can improve the response to chemotherapy drugs to improve the prognosis of patients with osteosarcoma are urgently needed. Cordycepin has recently emerged as a promising antitumor drug candidate. This study aims to explore the effect of cordycepin in suppressing osteosarcoma in vivo and in vitro and the synergistic effect of cordycepin combined with cisplatin and to demonstrate the underlying molecular mechanism. METHODS: CCK-8 assay was performed to investigate the inhibition effect of cordycepin combined with cisplatin in osteosarcoma cell lines. The colony formation and invasion abilities were measured by colony formation assay and Transwell assay. Osteosarcoma cells apoptosis was detected by flow cytometry. Western blot analysis were used to detect the expression of cell apoptosis-related proteins and AMPK and AKT/mTOR signaling pathway-related proteins. Finally, we performed the in vivo animal model to further explore whether cordycepin and cisplatin exert synergistic antitumor effects. RESULTS: Notably, we found that treatment with cordycepin inhibited cell proliferation, invasion, and induced apoptosis in osteosarcoma cells in vitro and in vivo. Moreover, the combination of cordycepin and cisplatin led to marked inhibition of osteosarcoma cell proliferation and invasion and promoted osteosarcoma cell apoptosis in vitro and in vivo. Mechanistically, we demonstrated that cordycepin enhanced the sensitivity of osteosarcoma cells to cisplatin by activating AMPK and inhibiting the AKT/mTOR signaling pathway. CONCLUSIONS: In brief, this study provides comprehensive evidence that cordycepin inhibits osteosarcoma cell growth and invasion and induces osteosarcoma cell apoptosis by activating AMPK and inhibiting the AKT/mTOR signaling pathway and enhances the sensitivity of osteosarcoma cells to cisplatin, suggesting that cordycepin is a promising treatment for osteosarcoma.
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The intracellular chaperone heat-shock protein 70 (Hsp70) can be secreted from cells, but its extracellular role is unclear, as the protein has been reported to both activate and suppress the innate immune response. Potential immunomodulatory receptors on myelomonocytic lineage cells that bind extracellular Hsp70 are not well defined. Siglecs are Ig-superfamily lectins on mammalian leukocytes that recognize sialic acid-bearing glycans and thereby modulate immune responses. Siglec-5 and Siglec-14, expressed on monocytes and neutrophils, share identical ligand-binding domains but have opposing signaling functions. Based on phylogenetic analyses of these receptors, we predicted that endogenous sialic acid-independent ligands should exist. An unbiased screen revealed Hsp70 as a ligand for Siglec-5 and Siglec-14. Hsp70 stimulation through Siglec-5 delivers an anti-inflammatory signal, while stimulation through Siglec-14 is pro-inflammatory. The functional consequences of this interaction are also addressed in relation to a SIGLEC14 polymorphism found in humans. Our results demonstrate that an endogenous non-sialic acid-bearing molecule can be either a danger-associated or self-associated signal through paired Siglecs, and may explain seemingly contradictory prior reports on extracellular Hsp70 action.
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Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/inmunología , Proteínas HSP70 de Choque Térmico/inmunología , Lectinas/inmunología , Monocitos/inmunología , Receptores de Superficie Celular/inmunología , Transducción de Señal/inmunología , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Línea Celular Tumoral , Células HEK293 , Proteínas HSP70 de Choque Térmico/genética , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Lectinas/genética , Monocitos/patología , Receptores de Superficie Celular/genética , Transducción de Señal/genéticaRESUMEN
Non-small-cell lung cancer (NSCLC), in which the NF-κB pathway is constitutively activated, is one of the most common malignancies. Herein, we identify an E3 ubiquitin ligase, tripartite motif-containing 37 (TRIM37), participating in the K63 polyubiquitination of TRAF2, which is a significant step in the activation of NF-κB signaling. Both the mRNA and the protein expression levels of TRIM37 were much higher in NSCLC cell lines and tissues than in normal bronchial epithelial cells and matched adjacent non-tumor tissues. TRIM37 expression correlated closely with clinical stage and poor survival in NSCLC. Overexpression of TRIM37 antagonized cisplatin-induced apoptosis, induced angiogenesis and proliferation, and increased the aggressiveness of NSCLC cells in vitro and in vivo, whereas inhibition of TRIM37 led to the opposite effects. Gene set enrichment analysis (GSEA) showed that TRIM37 expression significantly correlated with NF-κB signaling. Furthermore, we found that TRIM37 bound to TRAF2 and promoted K63-linked ubiquitination of TRAF2, sustaining the eventual activation of the NF-κB pathway. Mutation in the ring finger domain of TRIM37, a hallmark of E3 ubiquitin ligases, led to loss of the ability to promote K63 polyubiquitination of TRAF2 and activate NF-κB signaling. Taken together, our findings provide evidence that TRIM37 plays an important role in constitutive NF-κB pathway activation and could serve as a prognostic factor and therapeutic target in NSCLC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Carcinoma de Pulmón de Células no Pequeñas/enzimología , Neoplasias Pulmonares/enzimología , FN-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismo , Células A549 , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , FN-kappa B/genética , Proteínas Nucleares/genética , Fosforilación , Transducción de Señal , Factor 2 Asociado a Receptor de TNF/genética , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas , Ubiquitinación , Regulación hacia ArribaRESUMEN
Streptococcus agalactiae (group B Streptococcus [GBS]) is often a commensal bacterium that colonizes healthy adults asymptomatically and is a frequent inhabitant of the vaginal tract in women. However, in immunocompromised individuals, particularly the newborn, GBS may transition to an invasive pathogen and cause serious disease. Despite the use of the currently recommended intrapartum antibiotic prophylaxis for GBS-positive mothers, GBS remains a leading cause of neonatal septicemia and meningitis. To adapt to the various host environments encountered during its disease cycle, GBS possesses multiple two-component regulatory systems (TCSs). Here we investigated the contribution of a transcriptional regulator containing a LytTR domain, LtdR, to GBS pathogenesis. Disruption of the ltdR gene in the GBS chromosome resulted in a significant increase in bacterial invasion into human cerebral microvascular endothelial cells (hCMEC) in vitro as well as the greater penetration of the blood-brain barrier (BBB) and the development of meningitis in vivo Correspondingly, infection of hCMEC with the ΔltdR mutant resulted in increased secretion of the proinflammatory cytokines interleukin-8 (IL-8), CXCL-1, and IL-6. Further, using a mouse model of GBS vaginal colonization, we observed that the ΔltdR mutant was cleared more readily from the vaginal tract and also that infection with the ΔltdR mutant resulted in increased cytokine production from human vaginal epithelial cells. RNA sequencing revealed global transcriptional differences between the ΔltdR mutant and the parental wild-type GBS strain. These results suggest that LtdR regulates many bacterial processes that can influence GBS-host interactions to promote both bacterial persistence and disease progression.
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Infecciones Estreptocócicas/genética , Infecciones Estreptocócicas/fisiopatología , Activación Transcripcional/genética , Activación Transcripcional/fisiología , Virulencia/genética , Virulencia/fisiología , Animales , Regulación Bacteriana de la Expresión Génica , Humanos , RatonesRESUMEN
BACKGROUND: SOD1 is an abundant enzyme that has been studied as a regulator of the antioxidant defence system, and this enzyme is well known for catalyzing the dismutation of superoxide into hydrogen peroxide. However the SOD1 in the progress of NPC and underlying mechanisms remain unclear. METHODS: In NPC tissue samples, SOD1 protein levels were measured by Western blot and immunohistochemical (IHC) staining. mRNA levels and SOD1 activity were monitored by qRT-PCR and SOD activity kit, respectively. Kaplan-Meier survival analysis was performed to explore the relationship between SOD1 expression and prognosis of NPC. The biological effects of SOD1 were investigated both in vitro by CCK-8, clonogenicity and apoptosis assays and in vivo by a xenograft mice model. Western blotting, ROS assay and triglyceride assays were applied to investigate the underlying molecular mechanism of pro-survival role of SOD1 in NPC. RESULTS: We observed a significant upregulation of SOD1 in NPC tissue and high SOD1 expression is a predictor of poor prognosis and is correlated with poor outcome. We confirmed the pro-survival role of SOD1 both in vitro and in vivo. We demonstrated that these mechanisms of SOD1 partly exist to maintain low levels of the superoxide anion and to avoid the accumulation of lipid droplets via enhanced CPT1A-mediated fatty acid oxidation. CONCLUSIONS: The results of this study indicate that SOD1 is a potential prognostic biomarker and a promising target for NPC therapy.
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Metabolismo de los Lípidos , Carcinoma Nasofaríngeo/patología , Superóxido Dismutasa-1/metabolismo , Animales , Apoptosis , Carnitina O-Palmitoiltransferasa/metabolismo , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Ratones , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Pronóstico , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa-1/deficiencia , Superóxido Dismutasa-1/genéticaRESUMEN
Humans can incorporate the xenoglycan N-glycolylneuraminic acid (Neu5Gc) from the diet into reproductive tissues and secretions. Most humans also have circulating antibodies specific for this dietary xenoglycan. The potential for inflammation induced by incorporated Neu5Gc and circulating anti-Neu5Gc antibodies, termed xenosialitis, has been discussed as a factor influencing several human diseases. Potential effects of xenosialitis on human fertility remain unknown. Here, we investigate possible adverse effects of the presence of Neu5Gc on sperm or endometrium combined with anti-Neu5Gc antibodies in semen or uterine secretions in a mouse model. We use Cmah(-/-) mice, humanized for Neu5Gc deficiency. We find that the viability, migration, and capacitation of sperm with incorporated Neu5Gc are negatively affected when these are exposed to anti-Neu5Gc antibodies. In addition, we find that after copulation, activated uterine neutrophils and macrophages show increased phagocytosis of sperm in the presence of anti-Neu5Gc antibodies via the complement receptor 3 (C3R) and Fcγ I/II/III (Fc receptor). Furthermore, Neu5Gc in endometrial cells combined with the presence of anti-Neu5Gc antibodies alters the receptivity and decidualization of endometrial explants. These studies provide mechanistic insights on how Neu5Gc on sperm and/or endometrium combined with anti-Neu5Gc antibodies in semen and uterine fluid might contribute to unexplained human infertility.
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Ácidos Neuramínicos/efectos adversos , Sialadenitis , Animales , Modelos Animales de Enfermedad , Endometrio/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Ácidos Neuramínicos/farmacología , Receptores de Complemento/genética , Receptores de Complemento/metabolismo , Receptores Fc/genética , Receptores Fc/metabolismo , Sialadenitis/inducido químicamente , Sialadenitis/enzimología , Sialadenitis/genética , Espermatozoides/metabolismoRESUMEN
Selectins are a family of calcium-dependent, type I transmembrane, carbohydrate-binding glycoproteins. Selectins and their ligands are not only involved in physiological processes such as leukocyte homing and pathological processes such as cancer, but also play an essential role in the human implantation. L-selectin and its ligands participate in the adhesion of the blastocyst to the endometrium at the maternal-fetal interface. P-selectin and E-selectin are involved in immune recognition of maternal decidua to the embedded embryo as well as trophoblast migration within decidual spiral arterioles. Moreover, altered expression of selectins and their ligands are found to be associated with some abnormal pregnancies and infertilities. This review focuses on the current progress of research on the role of selectins and their ligands in the human implantation process.
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Implantación del Embrión/genética , Selectinas/metabolismo , Trofoblastos/metabolismo , Decidua/crecimiento & desarrollo , Decidua/metabolismo , Endometrio/crecimiento & desarrollo , Endometrio/metabolismo , Femenino , Humanos , Ligandos , Masculino , Embarazo , Selectinas/genéticaRESUMEN
Certain pathogenic bacteria are known to modulate the innate immune response by decorating themselves with sialic acids, which can engage the myelomonocytic lineage inhibitory receptor Siglec-9, thereby evading immunosurveillance. We hypothesized that the well-known up-regulation of sialoglycoconjugates by tumors might similarly modulate interactions with innate immune cells. Supporting this hypothesis, Siglec-9-expressing myelomonocytic cells found in human tumor samples were accompanied by a strong up-regulation of Siglec-9 ligands. Blockade of Siglec-9 enhanced neutrophil activity against tumor cells in vitro. To investigate the function of inhibitory myelomonocytic Siglecs in vivo we studied mouse Siglec-E, the murine functional equivalent of Siglec-9. Siglec-E-deficient mice showed increased in vivo killing of tumor cells, and this effect was reversed by transgenic Siglec-9 expression in myelomonocytic cells. Siglec-E-deficient mice also showed enhanced immunosurveillance of autologous tumors. However, once tumors were established, they grew faster in Siglec-E-deficient mice. In keeping with this, Siglec-E-deficient macrophages showed a propensity toward a tumor-promoting M2 polarization, indicating a secondary role of CD33-related Siglecs in limiting cancer-promoting inflammation and tumor growth. Thus, we define a previously unidentified impact of inhibitory myelomonocytic Siglecs in cancer biology, with distinct roles that reflect the dual function of myelomonocytic cells in cancer progression. In keeping with this, a human polymorphism that reduced Siglec-9 binding to carcinomas was associated with improved early survival in non-small-cell lung cancer patients, which suggests that Siglec-9 might be therapeutically targeted within the right time frame and stage of disease.