RESUMEN

Maintaining gut homeostasis requires a complex interplay between the nervous and immune systems and the microbiome, but the nature of their interactions remains unclear. Chiu and Benoist's teams employed designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetics to target specific neuronal cell types and evaluate their effects on both the gut immune system and the microbiota.

RESUMEN

Previous studies have found that ferroptosis plays an important role in a variety of neurological diseases. However, the precise role of ferroptosis in the multiple sclerosis patients remains uncertain. We defined and validated a computational metric of ferroptosis levels. The ferroptosis scores were computed using the AUCell method, which reflects the enrichment scores of ferroptosis-related genes through gene ranking. The reliability of the ferroptosis score was assessed using various methods, involving cells induced to undergo ferroptosis by six different ferroptosis inducers. Through a comprehensive approach integrating snRNA-seq, spatial transcriptomics, and spatial proteomics data, we explored the role of ferroptosis in multiple sclerosis. Our findings revealed that among seven sampling regions of different white matter lesions, the edges of active lesions exhibited the highest ferroptosis score, which was associated with activation of the phagocyte system. Remyelination lesions exhibit the lowest ferroptosis score. In the cortex, ferroptosis score were elevated in neurons, relevant to a variety of neurodegenerative disease-related pathways. Spatial transcriptomics demonstrated a significant co-localization among ferroptosis score, neurodegeneration and microglia, which was verified by spatial proteomics. Furthermore, we established a diagnostic model of multiple sclerosis based on 24 ferroptosis-related genes in the peripheral blood. Ferroptosis might exhibits a dual role in the context of multiple sclerosis, relevant to both neuroimmunity and neurodegeneration, thereby presenting a promising and novel therapeutic target. Ferroptosis-related genes in the blood that could potentially serve as diagnostic and prognostic markers for multiple sclerosis.

Asunto(s)

Ferroptosis , Esclerosis Múltiple , Proteómica , Ferroptosis/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Esclerosis Múltiple/metabolismo , Humanos , Proteómica/métodos , Transcriptoma , Microglía/metabolismo , Microglía/patología , Perfilación de la Expresión Génica , Biología Computacional/métodos , Neuronas/metabolismo , Neuronas/patología , Multiómica

RESUMEN

Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness.

Asunto(s)

Infecciones por Escherichia coli , Escherichia coli , Pulmón , Polisacáridos Bacterianos , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Animales , Femenino , Masculino , Ratones , Biopelículas , Escherichia coli/fisiología , Hipotermia/metabolismo , Hipotermia/patología , Inflamación/metabolismo , Inflamación/patología , Pulmón/microbiología , Pulmón/patología , Neumonía/microbiología , Neumonía/patología , Pseudomonas aeruginosa/fisiología , Células Receptoras Sensoriales , Polisacáridos Bacterianos/metabolismo , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/patología , Nociceptores/metabolismo

RESUMEN

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.

Asunto(s)

Encéfalo , Interferón Tipo I , Microglía , Animales , Ratones , Interferón Tipo I/metabolismo , Microglía/metabolismo , Neuronas/metabolismo , Pez Cebra , Encéfalo/citología , Encéfalo/crecimiento & desarrollo

RESUMEN

Natural killer (NK) cells, a major component of the innate immune system, have prominent immunoregulatory, antitumor proliferation, and antiviral activities. NK cells act as a double-edged sword with therapeutic potential in neurological autoimmunity. Emerging evidence has identified NK cells are involved in the development and progression of neuroimmunological diseases such as multiple sclerosis, neuromyelitis optica spectrum disorders, autoimmune encephalitis, Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and idiopathic inflammatory myopathy. However, the regulatory mechanisms and functional roles of NK cells are highly variable in different clinical states of neuroimmunological diseases and need to be further determined. In this review, we summarize the evidence for the heterogenic involvement of NK cells in the above conditions. Further, we describe cutting-edge NK-cell-based immunotherapy for neuroimmunological diseases in preclinical and clinical development and highlight challenges that must be overcome to fully realize the therapeutic potential of NK cells.

Asunto(s)

Enfermedades Autoinmunes , Enfermedad de Hashimoto , Esclerosis Múltiple , Humanos , Neuroinmunomodulación , Autoinmunidad , Células Asesinas Naturales

RESUMEN

The epithelial lining of the respiratory tract and intestine provides a critical physical barrier to protect host tissues against environmental insults, including dietary antigens, allergens, chemicals, and microorganisms. In addition, specialized epithelial cells communicate directly with hematopoietic and neuronal cells. These epithelial-immune and epithelial-neuronal interactions control host immune responses and have important implications for inflammatory conditions associated with defects in the epithelial barrier, including asthma, allergy, and inflammatory bowel diseases. In this review, we discuss emerging research that identifies the mechanisms and impact of epithelial-immune and epithelial-neuronal cross talk in regulating immunity, inflammation, and tissue homeostasis at mucosal barrier surfaces. Understanding the regulation and impact of these pathways could provide new therapeutic targets for inflammatory diseases at mucosal sites.

Asunto(s)

Células Epiteliales , Homeostasis , Inflamación , Neuronas , Humanos , Homeostasis/inmunología , Animales , Inflamación/inmunología , Células Epiteliales/inmunología , Neuronas/inmunología , Comunicación Celular/inmunología , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Membrana Mucosa/inmunología

RESUMEN

In 2023,numerous theoretical advancements and technological breakthroughs have been achieved in the field of immunology research.In this article,we summarized representative research achievements in the field of immunology both domestically and internationally in 2023,and discussed the challenges and opportunities for future research.

RESUMEN

Communication between the immune and the nervous system is essential for human brain development and homeostasis. Disruption of this intricately regulated crosstalk can lead to neurodevelopmental, psychiatric, or neurodegenerative disorders. While animal models have been essential in characterizing the role of neuroimmunity in development and disease, they come with inherent limitations due to species specific differences, particularly with regard to microglia, the major subset of brain resident immune cells. The advent of induced pluripotent stem cell (iPSC) technology now allows the development of clinically relevant models of the central nervous system that adequately reflect human genetic architecture. This article will review recent publications that have leveraged iPSC technology to assess neuro-immune interactions. First, we will discuss the role of environmental stressors such as neurotropic viruses or pro-inflammatory cytokines on neuronal and glial function. Next, we will review how iPSC models can be used to study genetic risk factors in neurological and psychiatric disorders. Lastly, we will evaluate current challenges and future potential for iPSC models in the field of neuroimmunity.

RESUMEN

Asthma is a common disease that seriously threatens public health. With significant developments in bronchoscopy, different interventional pulmonology techniques for refractory asthma treatment have been developed. These technologies achieve therapeutic purposes by targeting diverse aspects of asthma pathophysiology. However, even though these newer techniques have shown appreciable clinical effects, their differences in mechanisms and mutual commonalities still deserve to be carefully explored. Therefore, in this review, we summarized the potential mechanisms of bronchial thermoplasty, targeted lung denervation, and cryoablation, and analyzed the relationship between these different methods. Based on available evidence, we speculated that the main pathway of chronic airway inflammation and other pathophysiologic processes in asthma is sensory nerve-related neurotransmitter release that forms a "neuro-immunity crosstalk" and amplifies airway neurogenic inflammation. The mechanism of completely blocking neuro-immunity crosstalk through dual-ablation of both efferent and afferent fibers may have a leading role in the clinical efficacy of interventional pulmonology in the treatment of asthma and deserves further investigation.

RESUMEN

Biogenic amines are crucial signaling molecules that modulate various physiological life functions both in vertebrates and invertebrates. In humans, these neurotransmitters influence the innate and adaptive immunity systems. In this work, we analyzed whether the aminergic neurotransmission of dopamine, serotonin, and octopamine could have an impact on the humoral innate immune response of Drosophila melanogaster. This is a powerful model system widely used to uncover the insect innate immunity mechanisms which are also conserved in mammals. We found that the neurotransmission of all these amines positively modulates the Toll-responsive antimicrobial peptide (AMP) drosomycin (drs) gene in adult flies infected with the Micrococcus luteus bacterium. Indeed, we showed that either blocking the neurotransmission in their specific aminergic neurons by expressing shibirets (Shits) or silencing the vesicular monoamine transporter gene (dVMAT) by RNAi caused a significantly reduced expression of the Toll-responsive drs gene. However, upon M. luteus infection, the block of aminergic transmission did not alter the expression of AMP attacin genes responding to the immune deficiency (Imd) and Toll pathways. Overall, our results not only reveal a neuroimmune function for biogenic amines in humoral immunity but also further highlight the complexity of the network controlling AMP gene regulation.

RESUMEN

Acetylcholine (ACh) is one the major neurotransmitters in insects, whose role in mediating synaptic interactions between neurons in the central nervous system is well characterized. It also plays largely unexplored regulatory functions in non-neuronal tissues. Here we demonstrate that ACh signaling is involved in the modulation of the innate immune response of Drosophila melanogaster. Knockdown of ACh synthesis or ACh vesicular transport in neurons reduced the activation of drosomycin (drs), a gene encoding an antimicrobial peptide, in adult flies infected with a Gram-positive bacterium. drs transcription was similarly affected in Drosophila α7 nicotinic acetylcholine receptor, nAChRalpha7 (Dα7) mutants, as well as in flies expressing in the nervous system a dominant negative form (Dα7DN) of this specific receptor subunit. Interestingly, Dα7DN elicited a comparable response when it was expressed in non-neuronal tissues and even when it was specifically produced in the hemocytes. Consistently, full activation of the drs gene required Dα7 expression in these cells. Moreover, knockdown of ACh synthesis in non-neuronal cells affected drs expression. Overall, these findings uncover neural and non-neural cholinergic signals that modulate insect immune defenses and shed light on the role of hemocytes in the regulation of the humoral immune response.

Asunto(s)

Acetilcolina , Receptores Nicotínicos , Animales , Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Inmunidad Humoral , Neuronas/metabolismo , Receptores Nicotínicos/genética

RESUMEN

Gut microbiome is an important part of the human gut, which is closely related to human health and disease. Alzheimer's disease (AD) is a kind of neurodegenerative diseases, and its underlying pathogenesis has not been fully elucidated. In recent years, studies have shown obvious differences in gut microbiome composition between AD patients and healthy subjects. Comprehensive changes in gut microbiota composition may play a role in AD progression through the gut-brain axis. However, the mechanism of this interlinkage is not yet fully understood. In this review, we explore the mechanism of gut microbiota's influence in AD through gut-brain axis regulation.

RESUMEN

Mu-Opioid Receptors (MORs) are well-known for participating in analgesia, sedation, drug addiction, and other physiological functions. Although MORs have been related to neuroinflammation their biological mechanism remains unclear. It is suggested that MORs work alongside Toll-Like Receptors to enhance the release of pro-inflammatory mediators and cytokines during pathological conditions. Some cytokines, including TNF-α, IL-1ß and IL-6, have been postulated to regulate MORs levels by both avoiding MOR recycling and enhancing its production. In addition, Neurokinin-1 Receptor, also affected during neuroinflammation, could be regulating MOR trafficking. Therefore, inflammation in the central nervous system seems to be associated with altered/increased MORs expression, which might regulate harmful processes, such as drug addiction and pain. Here, we provide a critical evaluation on MORs' role during neuroinflammation and its implication for these conditions. Understanding MORs' functioning, their regulation and implications on drug addiction and pain may help elucidate their potential therapeutic use against these pathological conditions and associated disorders.

Asunto(s)

Morfina , Trastornos Relacionados con Sustancias , Humanos , Morfina/uso terapéutico , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Enfermedades Neuroinflamatorias , Receptores Opioides mu/metabolismo , Dolor/tratamiento farmacológico , Trastornos Relacionados con Sustancias/tratamiento farmacológico

RESUMEN

BACKGROUND: Dorsal Root Ganglia (DRG) neurons are derived from the neural crest and mainly innervate the skin, while Jugular Nodose Complex (JNC) neurons originate from the placode and innervate internal organs. These ganglia are composed of highly heterogeneous groups of neurons aimed at assessing and preserving homeostasis. Among other subtypes, nociceptor neurons are specialized in sensing and responding to environmental dangers. As form typically follows function, we hypothesized that JNC and DRG neurons would be phenotypically and transcriptomically different. METHODS: Mouse JNC and DRG neurons were cultured ex vivo. Using calcium imaging, qPCR and neurite outgrowth assay, we compared the sensitivity of JNC and DRG neurons. Using in-silico analysis of existing RNA sequencing datasets, we confronted our results to transcriptomic differences found between both ganglia. RESULTS: We found drastically different expression levels of Transient Receptor Potential (TRP) channels, growth factor receptors and neuropeptides in JNC and DRG neurons. Functionally, naïve JNC neurons' TRP channels are more sensitive to thermal cues than the ones from DRG neurons. However, DRG neurons showed increased TRP channel responsiveness, neuropeptide release and neurite outgrowth when exposed to Nerve Growth Factor (NGF). In contrast, JNC neurons preferentially responded to Brain-derived neurotrophic factor (BDNF). CONCLUSION: Our data show that JNC and DRG neurons are transcriptomically and functionally unique and that pain sensitivity is different across anatomical sites. Drugs targeting NGF signaling may have limited efficacy to treat visceral pain. Bioelectronics nerve stimulation should also be adjusted to the ganglia being targeted and their different expression profile.

RESUMEN

Bacteria and viruses are both important pathogens causing intestinal infections, and studies on their pathogenic mechanisms tend to focus on one pathogen alone. However, bacterial and viral co-infections occur frequently in clinical settings, and infection by one pathogen can affect the severity of infection by another pathogen, either directly or indirectly. The presence of synergistic or antagonistic effects of two pathogens in co-infection can affect disease progression to varying degrees. The triad of bacterial-viral-gut interactions involves multiple aspects of inflammatory and immune signaling, neuroimmunity, nutritional immunity, and the gut microbiome. In this review, we discussed the different scenarios triggered by different orders of bacterial and viral infections in the gut and summarized the possible mechanisms of synergy or antagonism involved in their co-infection. We also explored the regulatory mechanisms of bacterial-viral co-infection at the host intestinal immune interface from multiple perspectives.

Asunto(s)

Infecciones Bacterianas/inmunología , Coinfección/inmunología , Inmunidad Mucosa/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Virosis/inmunología , Animales , Coinfección/microbiología , Coinfección/virología , Humanos , Mucosa Intestinal/virología

RESUMEN

The pathogenesis of rosacea has not been fully elucidated. It is currently believed that genetic factors, local skin immune imbalance, neuroimmune and neurovascular dysfunction, skin barrier function abnormalities, microbiota imbalance, etc., are all involved in the occurrence and development of rosacea. This review summarizes research progress in the pathophysiological pathogenesis of rosacea.

RESUMEN

Most obsessive-compulsive disorder patients get sick in childhood, adolescence and early adulthood, which has a serious impact on their psychosocial function. Childhood and adolescence are critical period of neurological development. Affected by genetic and environmental factors, individuals often have neuronal damage, abnormal myelination, synaptic overpruning, abnormal synaptic connections and so forth. Pediatric obsessive-compulsive disorder is closely related to neurodevelopmental, which may involve genetic variation, immune activation, neurotransmitter disorders and functional and structural abnormalities of key brain regions in the cortico-striato-thalamo-cortical.With the development of neuroimaging, optogenetics and other advanced technologies, the dynamic development process of the brain has been further understood, and the etiological mechanism of pediatric obsessive-compulsive disorder has been further explored.This paper summarized the latest researches in this field, focusing on neurodevelopment, and expounds the possible pathophysiological mechanism of obsessive-compulsive disorder from the perspectives of neuroimmunology, neurostructure, neuroimaging, neurobiochemistry and other disciplines. It provides a new idea for the early accurate diagnosis, recognition and intervention of obsessive-compulsive disorder.

RESUMEN

BACKGROUND: Glioblastoma is a paradigm of cancer-associated immunosuppression, limiting the effects of immunotherapeutic strategies. Thus, identifying the molecular mechanisms underlying immune surveillance evasion is critical. Recently, the preferential expression of inhibitory natural killer (NK) cell receptor CD161 on glioma-infiltrating cytotoxic T cells was identified. Focusing on the molecularly annotated, large-scale clinical samples from different ethnic origins, the data presented here provide evidence of this immune modulator's essential roles in brain tumor biology. METHODS: Retrospective RNA-seq data analysis was conducted in a cohort of 313 patients with glioma in the Chinese Glioma Genome Atlas (CGGA) database and 603 patients in The Cancer Genome Atlas (TCGA) database. In addition, single-cell sequencing data from seven surgical specimens of glioblastoma patients and a model in which patient-derived glioma stem cells were cocultured with peripheral lymphocytes, were used to analyze the molecular evolution process during gliomagenesis. RESULTS: CD161 was enriched in high-grade gliomas and isocitrate dehydrogenase (IDH)-wildtype glioma. CD161 acted as a potential biomarker for the mesenchymal subtype of glioma and an independent prognostic factor for the overall survival (OS) of patients with glioma. In addition, CD161 played an essential role in inhibiting the cytotoxicity of T cells in glioma patients. During the process of gliomagenesis, the expression of CD161 on different lymphocytes dynamically evolved. CONCLUSION: The expression of CD161 was closely related to the pathology and molecular pathology of glioma. Meanwhile, CD161 promoted the progression and evolution of gliomas through its unique effect on T cell dysfunction. Thus, CD161 is a promising novel target for immunotherapeutic strategies in glioma treatment.

Asunto(s)

Glioma/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Progresión de la Enfermedad , Glioma/genética , Glioma/mortalidad , Glioma/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/inmunología , Inflamación , Isocitrato Deshidrogenasa/genética , Linfocitos Infiltrantes de Tumor/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/genética , Pronóstico , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología , Transcriptoma , Escape del Tumor

RESUMEN

Traumatic brain injury (TBI) is characterized by broad clinical symptoms in brain insult by external damages to the skull. TBI potentially leads to severe physical, cognitive, and emotional impairment. The complex biochemical reactions of inflammatory processes in TBI significantly influence brain function and clinical sequelae's overall severity. Mesenchymal stem cell therapy has become a promising therapeutic field of treatment for serious injuries due to its ability to regulate the inflammatory microenvironment. In this study, we aimed to investigate MSC's anti-inflammatory ability through regulating leukocyte, neutrophils, and inflammatory factors (IL-6, CRP, and TNF-a), thereby reducing the trauma in the TBI. Biological effects of autologous MNC and MSC cell transplantation have been studied in 40 patients with molded TBI, after being filtered according to appropriate criteria. All patients initially received MNCs and subsequently MSCs (both intravenously) followed by continuous monitoring during treatment (2 months) with clinical cognitive indicators. The results after transplantation MSC indicated that the majority of patients experienced improved health function in different degrees during the follow-up period. Lower serum levels of inflammatory factors, leukocytes, and neutrophils population were detected following the transplantation compared with the levels prior to treatment and with the control patients. No severe symptoms were observed in patients after transplantation, despite 3-4 death cases in each group. Overall, the present study suggests that transplantation of MSC possibly regulates inflammatory factors and appears to be safe in TBI treatment.

Asunto(s)

Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Encéfalo/metabolismo , Lesiones Encefálicas/terapia , Lesiones Traumáticas del Encéfalo/terapia , Humanos , Trasplante de Células Madre Mesenquimatosas/métodos

RESUMEN

The current clinical first-line treatment of neuropathic pain still considers only the nervous system as the target, and its therapeutic effect is limited. An increasing number of studies support the opinion that neuropathic pain is a result of the combined action of the sensory nervous system and the related immune system. Under physiological conditions, both the nervous system and the immune system can maintain homeostasis by adjusting the mitochondrial function when sensing noxious stimulation. However, in the case of neuropathic pain, mitochondrial regulatory dysfunction occurs, which may result from the decreased expression of SIRT1. In this study, we review the role of SIRT1 in neuropathic pain from the viewpoint of neuroimmunity.

Asunto(s)

Neuralgia , Sirtuina 1 , Humanos , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Sirtuina 1/metabolismo