Epigenetic Changes in Cerebrospinal Fluid and Blood of People with Neurosyphilis.

Epigenetic changes within immune cells may contribute to neuroinflammation during bacterial infection, but its role in neurosyphilis pathogenesis and response has not yet been established. We longitudinally analyzed DNA methylation and RNA expression changes in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs) from 11 participants with laboratory-confirmed NS (CSF VDRL positive) and 11 matched controls with syphilis without NS (non-NS). DNA methylation profiles from CSF and PBMCs of participants with NS significantly differed from those of participants with non-NS. Some genes associated with these differentially methylated sites had corresponding RNA expression changes in the CSF (111/1097, 10.1%), which were enriched in B-cell, cytotoxic-compounds, and insulin-response pathways. Despite antibiotic treatment, approximately 80% of CSF methylation changes persisted; suggesting that epigenetic scars accompanying NS may persistently affect immunity following infection. Future studies must examine whether these sequelae are clinically meaningful.

Splenic nociceptive neural connection promotes humoral immunity.

Recent work by Wu and colleagues unveiled a previously enigmatic population of spleen-innervating nociceptors from left T8-T13 dorsal root ganglia (DRGs) in mice. They found a specific DRG-spleen sensorineural connection that promotes humoral immunity via a CGRP-CALCRL/RAMP1 axis, providing a valuable target for immune regulation in local microenvironments.

TRPV1: The key bridge in neuroimmune interactions.

The nervous and immune systems are crucial in fighting infections and inflammation and in maintaining immune homeostasis. The immune and nervous systems are independent, yet tightly integrated and coordinated organizations. Numerous molecules and receptors play key roles in enabling communication between the two systems. Transient receptor potential vanilloid subfamily member 1 (TRPV1) is a non-selective cation channel, recently shown to be widely expressed in the neuroimmune axis and implicated in neuropathic pain, autoimmune disorders, and immune cell function. TRPV1 is a key bridge in neuroimmune interactions, allowing for smooth and convenient communication between the two systems. Here, we discuss the coordinated cross-talking between the immune and nervous systems and the functional role and the functioning manner of the TRPV1 involved. We suggest that TRPV1 provides new insights into the collaborative relationship between the nervous and immune systems, highlighting exciting opportunities for advanced therapeutic approaches to treating neurogenic inflammation and immune-mediated diseases.

Cytokine dysregulation in amnestic mild cognitive impairment.

The pathophysiology of amnestic Mild Cognitive Impairment (aMCI) is largely unknown, although some papers found signs of immune activation. To assess the cytokine network in aMCI after excluding patients with major depression (MDD) and to examine the immune profiles of quantitative aMCI (qMCI) and distress symptoms of old age (DSOA) scores. A case-control study was conducted on 61 Thai aMCI participants and 60 healthy old adults (both without MDD). The Bio-Plex Pro human cytokine 27-plex test kit was used to assay cytokines/chemokines/growth factors in fasting plasma samples. aMCI is characterized by a significant immunosuppression, and reductions in T helper 1 (Th)1 and T cell growth profiles, the immune-inflammatory responses system, interleukin (IL)1ß, IL6, IL7, IL12p70, IL13, GM-CSF, and MCP-1. These 7 cytokines/chemokines exhibit neuroprotective effects at physiologic concentrations. In multivariate analyses, three neurotoxic chemokines, CCL11, CCL5, and CXCL8, emerged as significant predictors of aMCI. Logistic regression showed that aMCI was best predicted by combining IL7, IL1ß, MCP-1, years of education (all inversely associated) and CCL5 (positively associated). We found that 38.2% of the variance in the qMCI score was explained by IL7, IL1ß, MCP-1, IL13, years of education (inversely associated) and CCL5 (positively associated). The DSOA was not associated with any immune data. An imbalance between lowered levels of neuroprotective cytokines and chemokines, and relative increases in neurotoxic chemokines are key factors in aMCI. Future MCI research should always control for the confounding effects of affective symptoms.

Cough and Itch: common mechanisms of irritation in the throat and skin.

Cough and itch are protective mechanisms in the body. Cough occurs as a reflex motor response to foreign body inhalation, while itch is a sensation that similarly evokes a scratch response to remove irritants from the skin. Both cough and itch can last for sustained periods, leading to debilitating chronic disorders that negatively impact quality of life. Understanding the parallels and differences between chronic cough and chronic itch may be paramount to developing novel therapeutic approaches. In this article, we identify connections in the mechanisms contributing to the complex cough and scratch reflexes and summarize potential shared therapeutic targets. An online search was performed using various search engines, including PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov from 1983 to 2024. Articles were assessed for quality, and those relevant to the objective were analyzed and summarized. The literature demonstrated similarities in the triggers, peripheral and central nervous system processing, feedback mechanisms, immunologic mediators, and receptors involved in the cough and itch responses, with the neuronal sensitization processes exhibiting the greatest parallels between cough and itch. Given the substantial impact on quality of life, novel therapies targeting similar neuroimmune pathways may apply to both itch and cough and provide new avenues for enhancing their management.

Neural and immune roles in osteoarthritis pain: Mechanisms and intervention strategies.

Pain is the leading symptom for most individuals with osteoarthritis (OA), a complex condition marked by joint discomfort. Recently, the dynamic interplay between the nervous and immune systems has become a focal point for understanding pain regulation. Despite this, there is still a substantial gap in our comprehensive understanding of the neuroimmune interactions and their effects on pain in OA. This review examines the bidirectional influences between immune cells and nerves in OA progression. It explores current approaches that target neuroimmune pathways, including promoting M2 macrophage polarization and specific neuronal receptor targeting, for effective pain reduction. Translational potential statement: This review provides a comprehensive overview of the mechanisms underlying the interplay between the immune system and nervous system during the progression of OA, as well as their contributions to pain. Additionally, it compiles existing intervention strategies targeting neuroimmunity for the treatment of OA pain. This information offers valuable insights for researchers seeking to address the challenge of OA pain.

Pathophysiology of Prurigo Nodularis: Neuroimmune Dysregulation and the Role of Type 2 Inflammation.

Prurigo nodularis (PN) is a chronic, inflammatory skin condition characterized by multiple, intensely pruritic, distinctive nodular lesions. Subsequent scratching can further intensify the pruritus, culminating in a self-reinforcing itch-scratch cycle, which drives lesion development. The latest data indicate dysregulation of the neuroimmune axis in PN pathogenesis, including the involvement of sensory neurons, key effector immune cells, proinflammatory cytokines, dermal fibroblasts, and pruritogens. In this review, we highlight evidence supporting the role of type 2 immune axis dysregulation in driving the clinical presentation of PN and discuss how related signaling pathways may offer effective therapeutic targets to control PN signs and symptoms.

The brain-heart-immune axis: a vago-centric framework for predicting and enhancing resilient recovery in older surgery patients.

Nearly all geriatric surgical complications are studied in the context of a single organ system, e.g., cardiac complications and the heart; delirium and the brain; infections and the immune system. Yet, we know that advanced age, physiological stress, and infection all increase sympathetic and decrease parasympathetic nervous system function. Parasympathetic function is mediated through the vagus nerve, which connects the heart, brain, and immune system to form, what we have termed, the brain-heart-immune axis. We hypothesize that this brain-heart-immune axis plays a critical role in surgical recovery among older adults. In particular, we hypothesize that the brain-heart-immune axis plays a critical role in the most common surgical complication among older adults: postoperative delirium. Further, we present heart rate variability as a measure that may eventually become a multi-system vital sign evaluating brain-heart-immune axis function. Finally, we suggest the brain-heart-immune axis as a potential interventional target for bio-electronic neuro-immune modulation to enhance resilient surgical recovery among older adults.

Cerebrospinal fluid characteristics of patients presenting for evaluation of pediatric acute-neuropsychiatric syndrome.

Objectives: This study characterizes cerebral spinal fluid (CSF) indices including total protein, the albumin quotient, IgG index and oligoclonal bands in patients followed at a single center for pediatric acute-neuropsychiatric syndrome (PANS) and other psychiatric/behavioral deteriorations. Methods: In a retrospective chart review of 471 consecutive subjects evaluated for PANS at a single center, navigational keyword search of the electronic medical record was used to identify patients who underwent lumbar puncture (LP) as part of the evaluation of a severe or atypical psychiatric deterioration. Psychiatric symptom data was ascertained from parent questionnaires and clinical psychiatric evaluations. Inclusion criteria required that subjects presented with psychiatric deterioration at the time of first clinical visit and had a lumbar puncture completed as part of their evaluation. Subjects were categorized into three subgroups based on diagnosis: PANS (acute-onset of severe obsessive compulsive disorder (OCD) and/or eating restriction plus two other neuropsychiatric symptoms), autoimmune encephalitis (AE), and "other neuropsychiatric deterioration" (subacute onset of severe OCD, eating restriction, behavioral regression, psychosis, etc; not meeting criteria for PANS or AE). Results: 71/471 (15.0 %) of patients underwent LP. At least one CSF abnormality was seen in 29% of patients with PANS, 45% of patients with "other neuropsychiatric deterioration", and 40% of patients who met criteria for autoimmune encephalitis. The most common findings included elevated CSF protein and/or albumin quotient. Elevated IgG index and IgG oligoclonal bands were rare in all three groups. Conclusion: Elevation of CSF protein and albumin quotient were found in pediatric patients undergoing LP for evaluation of severe psychiatric deteriorations (PANS, AE, and other neuropsychiatric deteriorations). Further studies are warranted to investigate blood brain barrier integrity at the onset of the neuropsychiatric deterioration and explore inflammatory mechanisms.

Unweaving type I interferons in age-related neuroinflammation.

Neuroinflammation is a feature of both neurodegenerative disease and normal brain aging. The roles of type I interferon (IFN-I) in the aged brain are incompletely understood. A recent article by Roy et al. reveals pervasive IFN-I activity in normal mouse brain aging, and highlights the importance of microglial IFN-I signaling in neuroinflammation.

Key actors in neuropathophysiology: The role of γδ T cells.

The neuroimmune axis has been the focus of many studies, with special emphasis on the interactions between the central nervous system and the different immune cell subsets. T cells are namely recognized to play a critical role due to their interaction with nerves, by secreting cytokines and neurotrophins, which regulate the development, function, and survival of neurons. In this context, γδ T cells are particularly relevant, as they colonize specific tissues, namely the meninges, and have a wide variety of complex functions that balance physiological systems. Notably, γδ T cells are not only key components for maintaining brain homeostasis but are also responsible for triggering or preventing inflammatory responses in various pathologies, including neurodegenerative diseases as well as neuropsychiatric and developmental disorders. Here, we provide an overview of the current state of the art on the contribution of γδ T cells in neuropathophysiology and delve into the molecular mechanisms behind it. We aim to shed light on γδ T cell functions in the central nervous system while highlighting upcoming challenges in the field and providing new clues for potential therapeutic strategies.

The novel schizophrenia subgroup "major neurocognitive psychosis" is validated as a distinct class through the analysis of immune-linked neurotoxicity biomarkers and neurocognitive deficits.

Background: Using machine learning methods based on neurocognitive deficits and neuroimmune biomarkers, two distinct classes were discovered within schizophrenia patient samples. Increased frequency of psychomotor retardation, formal thought disorders, mannerisms, psychosis, hostility, excitation, and negative symptoms defined the first subgroup, major neurocognitive psychosis (MNP). Cognitive deficits in executive functions and memory and diverse neuroimmune aberrations were other MNP features. Simple neurocognitive psychosis (SNP) was the less severe phenotype. Aims: The study comprised a sample of 40 healthy controls and 90 individuals diagnosed with schizophrenia, divided into MNP and SNP based on previously determined criteria. Soft Independent Modelling of Class Analogy (SIMCA) was performed using neurocognitive test results and measurements of serum M1 macrophage and T helper-17 cytokines as discriminatory/modelling variables. The model-to-model distances between controls and MNP + SNP and between MNP and SNP were computed, and the top discriminatory variables were established. Results: A notable SIMCA distance of 146.1682 was observed between MNP + SNP and the control group. The top-3 discriminatory variables were lowered motor speed, an activated T helper-17 axis, and lowered working memory. This study successfully differentiated MNP from SNP yielding a SIMCA distance of 19.3. M1 macrophage activation, lowered verbal fluency, and executive functions were the prominent features of MNP versus SNP. Discussion: Based on neurocognitive assessments and the immune-linked neurotoxic M1 and T helper-17 profiles, we found that MNP and SNP are qualitatively distinct classes. Future biomarker research should focus on examining biomarkers specifically in the MNP and SNP subgroups, rather than in the schizophrenia group.

Spatiotemporal Dysregulation of Neuron-Glia Related Genes and Pro-/Anti-Inflammatory miRNAs in the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein (Gfap), triggering receptor expressed on myeloid cells (Trem2) and cystatin F (Cst7), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha (Cebpa) and myelin proteolipid protein (Plp) in the PFC, as well as for BCL2 apoptosis regulator (Bcl2) and purinergic receptor P2Y12 (P2yr12) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells.

Acute systemic macrophage depletion in osteoarthritic mice alleviates pain-related behaviors and does not affect joint damage.

Background: Osteoarthritis (OA) is a painful degenerative joint disease and a leading source of years lived with disability globally due to inadequate treatment options. Neuroimmune interactions reportedly contribute to OA pain pathogenesis. Notably, in rodents, macrophages in the DRG are associated with onset of persistent OA pain. Our objective was to determine the effects of acute systemic macrophage depletion on pain-related behaviors and joint damage using surgical mouse models in both sexes. Methods: We depleted CSF1R+ macrophages by treating male macrophage Fas-induced apoptosis (MaFIA) transgenic mice 8- or 16-weeks post destabilization of the medial meniscus (DMM) with AP20187 or vehicle control (10 mg/kg i.p., 1x/day for 5 days), or treating female MaFIA mice 12 weeks post partial meniscectomy (PMX) with AP20187 or vehicle control. We measured pain-related behaviors 1-3 days before and after depletion, and, 3-4 days after the last injection we examined joint histopathology and performed flow cytometry of the dorsal root ganglia (DRGs). In a separate cohort of male 8-week DMM mice or age-matched naïve vehicle controls, we conducted DRG bulk RNA-sequencing analyses after the 5-day vehicle or AP20187 treatment. Results: Eight- and 16-weeks post DMM in male mice, AP20187-induced macrophage depletion resulted in attenuated mechanical allodynia and knee hyperalgesia. Female mice showed alleviation of mechanical allodynia, knee hyperalgesia, and weight bearing deficits after macrophage depletion at 12 weeks post PMX. Macrophage depletion did not affect the degree of cartilage degeneration, osteophyte width, or synovitis in either sex. Flow cytometry of the DRG revealed that macrophages and neutrophils were reduced after AP20187 treatment. In addition, in the DRG, only MHCII+ M1-like macrophages were significantly decreased, while CD163+MHCII- M2-like macrophages were not affected in both sexes. DRG bulk RNA-seq revealed that Cxcl10 and Il1b were upregulated with DMM surgery compared to naïve mice, and downregulated in DMM after acute macrophage depletion. Conclusions: Acute systemic macrophage depletion reduced the levels of pro-inflammatory macrophages in the DRG and alleviated pain-related behaviors in established surgically induced OA in mice of both sexes, without affecting joint damage. Overall, these studies provide insight into immune cell regulation in the DRG during OA.

Neuroimmune and neuroinflammation response for traumatic brain injury.

Traumatic brain injury (TBI) is one of the major diseases leading to mortality and disability, causing a serious disease burden on individuals' ordinary lives as well as socioeconomics. In primary injury, neuroimmune and neuroinflammation are both responsible for the TBI. Besides, extensive and sustained injury induced by neuroimmune and neuroinflammation also prolongs the course and worsens prognosis of TBI. Therefore, this review aims to explore the role of neuroimmune, neuroinflammation and factors associated them in TBI as well as the therapies for TBI. Thus, we conducted by searching PubMed, Scopus, and Web of Science databases for articles published between 2010 and 2023. Keywords included "traumatic brain injury," "neuroimmune response," "neuroinflammation," "astrocytes," "microglia," and "NLRP3." Articles were selected based on relevance and quality of evidence. On this basis, we provide the cellular and molecular mechanisms of TBI-induced both neuroimmune and neuroinflammation response, as well as the different factors affecting them, are introduced based on physiology of TBI, which supply a clear overview in TBI-induced chain-reacting, for a better understanding of TBI and to offer more thoughts on the future therapies for TBI.

Research on the Mechanism of Buyang Huanwu Decoction in the Amelioration of Age-Associated Memory Impairment Based on the "Co-occurrence Network Regulation of Intestinal Microecology-Host Metabolism-Immune Function".

ETHNOPHARMACOLOGICAL RELEVANCE: Brain aging can promote neuronal damage, contributing to aging-related diseases like memory dysfunction. Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine formula known for tonifying qi and activating blood circulation, shows neuroprotective properties. Despite this, the specific mechanism by which BYHWD improves age-associated memory impairment (AAMI) has not been explored in existing literature. AIM OF THE STUDY: This study aimed to investigate the mechanism of BYHWD in the improvement of AAMI based on the "co-occurrence network regulation of intestinal microecology-host metabolism- immune function". MATERIALS AND METHODS: Firstly, D-galactose was performed to induce a rat model of AAMI. Learning and memory deficits was assessed by the Morris water maze test. H&E and Nissl staining were used to observe the pathological changes in neurons in the hippocampus of rats. Meanwhile, the levels of pro-inflammatory cytokines and the activation of antioxidant enzymes in rat serum were measured using ELISA. Finally, an integrated pharmacological approach was applied to explore the potential mechanism of BYHWD in improving AAMI. RESULTS: Our results indicated that BYHWD significantly mitigated the pathological structure of the hippocampus, reversed the levels of IL-6, TNF-α, GSH, and CAT in the serum, and improved learning and memory in aging rats. Transcriptomics combined with network pharmacology showed that energy metabolism and the inflammatory response were the key biological pathways for BYHWD to ameliorate AAMI. Integrative analysis of the microbiome and metabolomics revealed that BYHWD has the potential to restore the balance of abundance between probiotics and harmful bacteria, and ameliorate the reprogramming of energy metabolism caused by aging in the brain. The co-occurrence network analysis demonstrated that a strong correlation between the treatment of AAMI and the stability of intestinal microecology, host metabolism, and immune network. CONCLUSION: The findings of this study collectively support the notion that BYHWD has a superior therapeutic effect in an AAMI rat model. The mechanism involves regulating the "intestinal microecology-metabolism-immune function co-occurrence network" system to restore the composition of gut microbiota and metabolites. This further improves the metabolic phenotype of brain tissue and maintains the homeostasis of central nervous system's immunity, leading to an improvement in AAMI. Consequently, this study offers a unique perspective on the prevention and treatment of AAMI. And, BYHWD is also considered to be a promising preclinical treatment for improving AAMI.

Versatile conductive hydrogel orchestrating neuro-immune microenvironment for rapid diabetic wound healing through peripheral nerve regeneration.

Diabetic wound (DW), notorious for prolonged healing processes due to the unregulated immune response, neuropathy, and persistent infection, poses a significant challenge to clinical management. Current strategies for treating DW primarily focus on alleviating the inflammatory milieu or promoting angiogenesis, while limited attention has been given to modulating the neuro-immune microenvironment. Thus, we present an electrically conductive hydrogel dressing and identify its neurogenesis influence in a nerve injury animal model initially by encouraging the proliferation and migration of Schwann cells. Further, endowed with the synergizing effect of near-infrared responsive release of curcumin and nature-inspired artificial heterogeneous melanin nanoparticles, it can harmonize the immune microenvironment by restoring the macrophage phenotype and scavenging excessive reactive oxygen species. This in-situ formed hydrogel also exhibits mild photothermal therapy antibacterial efficacy. In the infected DW model, this hydrogel effectively supports nerve regeneration and mitigates the immune microenvironment, thereby expediting the healing progress. The versatile hydrogel exhibits significant therapeutic potential for application in DW healing through fine-tuning the neuro-immune microenvironment.

Peripheral and central regulation of neuro-immune crosstalk.

The neural and immune systems sense and respond to external stimuli to maintain tissue homeostasis. These systems do not function independently but rather interact with each other to effectively exert biological actions and prevent disease pathogenesis, such as metabolic, inflammatory, and infectious disorders. Mutual communication between these systems is also affected by tissue niche-specific signals that reflect the tissue environment. However, the regulatory mechanisms underlying these interactions are not completely understood. In addition to the peripheral regulation of neuro-immune crosstalk, recent studies have reported that the central nervous system plays essential roles in the regulation of systemic neuro-immune interactions. In this review, we provide an overview of the molecular basis of peripheral and systemic neuro-immune crosstalk and explore how these multilayered interactions are maintained.

Neuroimmune Crossroads: The Interplay of the Enteric Nervous System and Intestinal Macrophages in Gut Homeostasis and Disease.

A defining unique characteristic of the gut immune system is its ability to respond effectively to foreign pathogens while mitigating unnecessary inflammation. Intestinal macrophages serve as the cornerstone of this balancing act, acting uniquely as both the sword and shield in the gut microenvironment. The GI tract is densely innervated by the enteric nervous system (ENS), the intrinsic nervous system of the gut. Recent advances in sequencing technology have increasingly suggested neuroimmune crosstalk as a critical component for homeostasis both within the gut and in other tissues. Here, we systematically review the ENS-macrophage axis. We focus on the pertinent molecules produced by the ENS, spotlight the mechanistic contributions of intestinal macrophages to gut homeostasis and inflammation, and discuss both existing and potential strategies that intestinal macrophages use to integrate signals from the ENS. This review aims to elucidate the complex molecular basis governing ENS-macrophage signaling, highlighting their cooperative roles in sustaining intestinal health and immune equilibrium.