Sympathetic Neurotransmission Research Articles

Macrophage NLRP3 inflammasome mediates the effects of sympathetic nerve on cardiac remodeling in obese rats

Obesity-associated cardiac remodeling is characterized by cardiac sympathetic nerve over-activation and pro-inflammatory macrophage infiltration. We identified norepinephrine (NE), a sympathetic neurotransmitter, as a pro-inflammatory effector to activate macrophage NLRP3 inflammasome, which contributed to cardiac inflammation. In vivo, Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 12 weeks to establish obese rat models. Obese rats exhibited marked cardiac hypertrophy compared to normal rats. The expression of NLRP3 and interleukin (IL)-1β was upregulated, accompanied by CD68+NLRP3+ macrophage infiltration in the hearts of the obese rats. The obese rats also showed increased sympathetic nerve activity. β-adrenergic receptor (AR) inhibition mitigated these changes. In vitro, sympathetic neurotransmitter NE significantly exacerbated palmitic acid (PA)-induced macrophage polarization toward pro-inflammatory type and NLRP3 inflammasome activation in THP-1 macrophages. It was further found that the pro-inflammatory role of NE is dependent on the activation of protein kinase A (PKA) and subsequently inhibition of β-arrestin2, which is an important regulator of the nuclear factor-kappa B (NF-κB) pathway.This study identifies the neuro-immune axis as an important mediator in obesity-associated cardiac remodeling. Targeting the neuro-immune system may open therapeutic opportunities for the treatment of cardiac remodeling in obesity.

TH17/Treg lymphocyte balance is regulated by beta adrenergic and cAMP signaling

BackgroundPost-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a mouse model of repeated social defeat stress (RSDS) that recapitulates certain features of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear. MethodsUsing a modified version of RSDS that allows for both males and females, as well as ex vivo models of T-lymphocyte polarization, we assessed the impact and mechanism of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte differentiation to IL-17A-producing subtypes (i.e., TH17). ResultsOnly pharmacological inhibition of the beta 1 and 2 adrenergic receptors (β1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g.,IL-6, TNF-α, and IL-10). This finding was confirmed using RSDS with both global β1/2 receptor knock-out mice, as well as by adoptively transferring β1/2 knock-out T-lymphocytes into immunodeficient hosts. Ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of β1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Furthermore, cyclic AMP (cAMP) was demonstrated to be mechanistically involved in driving IL-17A production in T-lymphocytes, and amplifying cAMP signaling could restore IL-17A deficits caused by the absence of β1/2 signaling. Last, removal of β1/2 and cAMP signaling, even in IL-17A polarizing conditions, promoted regulatory T-lymphocyte (Treg) polarization, suggesting adrenergic signaling plays a role in the switching between pro- and anti-inflammatory T-lymphocyte subtypes. ConclusionsOur data depict a novel role for β1/2 adrenergic and cAMP signaling in the balance of TH17/Treg lymphocytes. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.

Phenotypic and functional disparities in perivascular adipose tissue.

The adipose tissue surrounding blood vessels is known as perivascular adipose tissue (PVAT), which represents a distinct ectopic fat depot that adheres to the majority of the vasculature. In recent years, owing to its unique location and function, PVAT has been regarded as a new type of adipose tissue distinct from traditional visceral fat. It releases adipokines with vasoconstrictive functions, which regulate vascular function through paracrine and endocrine mechanisms. Interestingly, PVAT can be categorized as white, brown or a mixture of both depending on its anatomical location. Brown adipose tissue (BAT) is located adjacent to the thoracic aorta in rodents, while a mix of brown and white tissue surrounds the abdominal aorta. PVAT exhibits regional phenotypic differences in different parts of the vasculature bed, which may lead to heterogeneity in the secretion profiles and norepinephrine (NE) content in regional PVAT and subsequently affect the regulation of specific adipokine signaling pathways in regional PVAT, resulting in differences in the regulation of vascular function. The aim of this review was to explore the potential factors that influence the anticontractile function of regional PVAT in the vasculature, including the heterogeneity of regional PVAT, the anticontractile function mediated by endothelial nitric oxide synthase (eNOS) in regional PVAT, the activity of the adiponectin-eNOS pathway in regional PVAT adipocytes, and the concentration of the sympathetic neurotransmitter NE in regional PVAT.

Sex influence on serotonergic modulation of the vascular noradrenergic drive in rats.

In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho-inhibition and sympatho-excitation, mainly via 5-HT1D/1A and 5-HT3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5-HT sympatho-modulatory role in female rats, characterising the 5-HT receptors involved. Female Wistar (14- to 16-week-old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1-5 Hz) or i.v. noradrenaline (0.01-0.5 μg·kg-1). 5-HT-related drug effects on adrenergic system were determined. Age-matched male rats were used as control. Basal MBP in females was lower than in male rats, whereas electrical-induced increases in MBP were similar. In females, 5-HT exerted a dose-dependent inhibition on the sympathetic-evoked vasoconstrictions, that was reproduced by some agonists; 5-CT (5-HT1/5/7) and L-694,247 (5-HT1D), whereas the selective 5-HT2A/2B/2C (α-methyl-5-HT) and 5-HT3 agonist (1-PBG) increased the electrically-produced vasopressor responses. None of the other drugs tested (targeting 5-HT1A/1B/1F, 5-HT2B/2C, 5-HT4, 5-HT5A or 5-HT7) modified these vasoconstrictions. Only 1-PBG (5-HT3) modified the vasoconstrictions induced by exogenous noradrenaline. In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5-HT1D receptor activation, whereas pre and/or postjunctional 5-HT3 and prejunctional 5-HT2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex-differential therapeutic strategies for treating cardiovascular conditions.

Mouse liver blood flow is regulated by hepatic stellate cells in response to the sympathetic neurotransmitter norepinephrine

BackgroundThere is no clear information on the regulation of liver blood flow by the autonomic nervous system. We conducted this study to investigate whether quiescent hepatic stellate cells (qHSCs) regulate liver blood flow in response to the sympathetic neurotransmitter norepinephrine (NE). MethodsqHSCs isolated from mice were cultured in Dulbecco's modified Eagle medium without fetal bovine serum for 1 day on collagen gel. NE-induced qHSC contraction was evaluated using the quantitative single-cell contraction measurement method that we had developed previously. For the measurement of liver perfusion pressure in situ, a buffer solution was perfused from the portal vein in mice. ResultsNE-induced a reversible contraction of qHSCs. This contraction was suppressed by the nonmuscle myosin II inhibitor blebbistatin, the myosin light chain kinase inhibitor ML-9, the Rho kinase inhibitor H-1152, the calmodulin inhibitor W-7, the store-operated calcium channel inhibitor YM-58483, and the IP3 receptor inhibitor xestospongin C. In contrast, the transient receptor potential C channel inhibitor SKF96365 did not affect the NE-induced contraction. ConclusionThese results suggest that qHSCs contract in response to NE. New & noteworthyThe present study provides direct evidence for the first time that norepinephrine (NE) induces a reversible contraction of isolated single quiescent hepatic stellate cells (qHSCs) and further suggests that the NE-mediated qHSC contraction participates in the regulation of liver blood flow in vivo.

Beta-adrenergic signaling and T-lymphocyte-produced catecholamines are necessary for interleukin 17A synthesis.

Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a preclinical model of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear. Using a modified version of repeated social defeat stress (RSDS) that allows for both males and females, we assessed the impact of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte IL-17A generation. Additionally, we explored the impact of adrenergic signaling and T-lymphocyte-produced catecholamines on both CD4+ and CD8+ T-lymphocytes polarized to IL-17A-producing phenotypes ex vivo. Only pharmacological inhibition of the beta 1 and 2 adrenergic receptors (β1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IL-10). This finding was confirmed using RSDS with both global β1/2 receptor knock-out mice, as well as by adoptively transferring β1/2 knock-out T-lymphocytes into immunodeficient hosts. Furthermore, ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of β1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Indeed, pharmacological depletion of catecholamines both in vivo and ex vivo abrogated T-lymphocyte IL-17A production demonstrating the importance of immune-generated neurotransmission in pro-inflammatory cytokine generation. Our data depict a novel role for β1/2 adrenergic receptors and autologous catecholamine signaling during T-lymphocyte IL-17A production. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.

The transcriptome profiling of diseased mouse aortas discloses a dysregulation of the sympathetic neurotransmission in atherosclerosis

Previous reports suggest an association between the development of atherosclerosis and alterations in the aortic sympathetic nervous system, but there is no agreement on whether atherosclerotic plaques are accompanied by increased or decreased sympathetic innervation in the arterial wall.In the present study, the aortic transcriptional profile of mice with different predisposition to atherosclerosis was investigated to clarify how the expression of genes involved in sympathetic neurotransmission varied.Eight-week-old C57Bl/6J control mice, Apoe knockout mice (EKO), EKO mice overexpressing human apoA-I (EKO/hA-I) and double Apoe/Apoa1 knockout mice (DKO) mice were fed either a standard rodent diet or a Western-type diet for 22 weeks. Atherosclerosis was quantified, and the aortic transcriptome was analyzed by RNAseq. Western-type diet administration deeply modified the aortic transcriptome. In the genetically modified atherosclerosis-prone mouse lines, an upregulated expression of genes associated with the immunomodulatory response was observed, paralleled by a downregulated expression of the genes related to sympathetic nervous system. Functional enrichment analysis indicated that the presence of advanced atherosclerosis was accompanied by reduced neuronal generation, modulation of synapse chemical transmission, and catecholamine biosynthesis, supporting a relationship between atherosclerosis, dyslipidemia, and sympathetic neurotransmission.

Mechanisms of norepinephrine induced calcium responses in perivascular adipocytes

Perivascular adipose tissue (PVAT) has emerged as a key regulator of vascular tone and blood pressure making it an intriguing avenue for research related to pervasive aliments such as high blood pressure. PVAT surrounds the majority of blood vessels where it releases anticontractile factors such as nitric oxide, hydrogen sulfide, adiponectin, and leptin. The production of these anticontractile factors is driven by the sympathetic neurotransmitter norepinephrine (NE), but there is little known about mechanisms which mediate the NE response in PVAT. Based on the known role of beta adrenergic receptors in other fat depots, we hypothesized that NE primarily acts on beta II and III adrenergic receptors. Adiponectin cre positive transgenic mice genetically encoded with calcium indicators were used for live calcium imaging. The peaks of the NE response before and after the receptor antagonists were applied by comparing the change in fluorescence. The beta receptor antagonist, SR 59230A, was used at 6.5μM to block both beta II and III receptors. In addition, the A1a antagonist RS 100329 at 1μM was used to block alpha receptors present. Both antagonists were chosen because they have previously used in the literature successfully at these concentrations. The beta II and beta III antagonist significantly decreased the calcium response in the mesenteric PVAT (p=<0.0001) by 33% and a 27% significant decrease in the subcutaneous fat pad (p=). The alpha 1a antagonist significantly decreased the calcium response in the mesenteric PVAT (p=<0.0001) by 59%, as well as an 86% significant decrease in the subcutaneous fat pad (p=<0.0001), and a 60% significant decrease in the aortic PVAT (p=<0.0001). The combination of both antagonists significantly decreased the calcium response in the mesenteric PVAT (p=<0.0001) by 33%, as well as 46% in the subcutaneous fat pad (p=<0.0001), and 37% decrease in the aortic PVAT (p=0.0354). Both beta and alpha adrenergic receptors are present in mesenteric PVAT and subcutaneous fat, while primarily alpha adrenergic receptors are present in aortic PVAT. These observations suggest the mechanisms responsible for NE induced calcium responses are tissue dependent. HL152951. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Neuropeptide Y affects B-cell activation functions

Introduction: Sympathetic nerves secrete neurotransmitters in response to pathogenic organisms in various immunological contexts. Most studies have focused on norepinephrine (NE) which has shown numerous immunomodulatory effects involving pro- and anti-inflammatory responses. However, sympathetic neurons contain also varicosities where neuropeptides, mainly neuropeptide Y (NPY), are stored. NPY play roles in various physiological processes, including regulating metabolism, vascular function, and immune function but little is known on its action during bacterial respiratory infection. The regulation of its secretion and its impact on the immune system during infection remains unclear. We investigated the role of NPY in B-cell responses during bacterial infection. Methods: Naïve B-cells isolated from mice splenocytes (2M/2F) were stimulated with IL-4 and LPS, along with NE or NPY. After 96 hours, cells were stained and analyzed by flow cytometry and transcripts were isolated for quantitative real-time PCR. Media was collected until immunoglobulin analysis. To investigate NPY role during infection, we used a mice model of bacterial lung infection. Mice were intranasally exposed twice with streptococcus pneumoniae (serotype 19F on day 0: 104 CFU and on day 9: 108 CFU); experiments took place 16 hours later. Control animals were infused with vehicle only. Results: Apart from beta2-adrenergic receptor, isolated B-cells were found to express alpha2- and beta1-adrenergic receptor transcripts. In vitro stimulation of B-cell with IL-4 and LPS (T-cell independent activation) downregulated beta-adrenergic and upregulated alpha2-adrenergic, as well as NPY receptors (Npy1r, Npy2r, Npy4r, Npy5r). Unlike NE, NPY has shown to affect B-cell proliferation and drastically increases IgG positive-cells during stimulation. However, neither NE nor NPY seem to regulate IgG release in this condition. In vivo experiments indicate that NPY level increased in the lung in response to streptococcal challenge, contrasting with the unchanged levels of NE. Conclusion: Our findings contribute to our understanding of how sympathetic neurotransmitters regulates B-cell expansion, memory, and antibody production during infection. Furthermore, our research gives new insights into the function(s) and antimicrobial capacity of neuropeptide Y. These findings allow for the development of new and more effective therapeutic strategies for invasive bacterial infections. 1R21AI159221, UCOP TRDRP T32KT4708. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

β-Receptor blocker enhances the anabolic effect of PTH after osteoporotic fracture

The autonomic nervous system plays a crucial role in regulating bone metabolism, with sympathetic activation stimulating bone resorption and inhibiting bone formation. We found that fractures lead to increased sympathetic tone, enhanced osteoclast resorption, decreased osteoblast formation, and thus hastened systemic bone loss in ovariectomized (OVX) mice. However, the combined administration of parathyroid hormone (PTH) and the β-receptor blocker propranolol dramatically promoted systemic bone formation and osteoporotic fracture healing in OVX mice. The effect of this treatment is superior to that of treatment with PTH or propranolol alone. In vitro, the sympathetic neurotransmitter norepinephrine (NE) suppressed PTH-induced osteoblast differentiation and mineralization, which was rescued by propranolol. Moreover, NE decreased the PTH-induced expression of Runx2 but enhanced the expression of Rankl and the effect of PTH-stimulated osteoblasts on osteoclastic differentiation, whereas these effects were reversed by propranolol. Furthermore, PTH increased the expression of the circadian clock gene Bmal1, which was inhibited by NE-βAR signaling. Bmal1 knockdown blocked the rescue effect of propranolol on the NE-induced decrease in PTH-stimulated osteoblast differentiation. Taken together, these results suggest that propranolol enhances the anabolic effect of PTH in preventing systemic bone loss following osteoporotic fracture by blocking the negative effects of sympathetic signaling on PTH anabolism.

Generation of Functional and Mature Sympathetic Neurons from Human Pluripotent Stem Cells via a Neuroepithelial Route.

The sympathetic nervous system (SNS) is a crucial branch of the autonomic nervous system (ANS) that is responsible for regulating visceral function and various physiological processes. Dysfunction of the SNS can lead to various diseases, such as hypertension and metabolic disorders. However, obtaining sympathetic neurons from human tissues for research is challenging. The current research aimed at recapitulating the process of human sympathetic neuron development and achieved the successful establishment of a stepwise, highly efficient in vitro differentiation protocol. This protocol facilitated the generation of functional and mature sympathetic neurons from human pluripotent stem cells (hPSCs) using a chemical-defined induction medium. Initially, each differentiation stage was refined to derive sympathoadrenal progenitors (SAPs) from hPSCs through neural epithelial cells (NECs) and trunk neural crest stem cells (NCSCs). hPSC-derived SAPs could be expanded in vitro for at least 12 passages while maintaining the expression of SAP-specific transcription factors and neuronal differentiation potency. SAPs readily generated functional sympathetic neurons (SymNs) when cultured in the neuronal maturation medium for 3-4 weeks. These SymNs expressed sympathetic markers, exhibited electrophysiological properties, and secreted sympathetic neurotransmitters. More importantly, we further demonstrated that hPSC-derived SymNs can efficiently regulate the adipogenesis of human adipose-derived stem cells (ADSCs) and lipid metabolism in vitro. In conclusion, our study provided a simple and robust protocol for generating functional sympathetic neurons from hPSCs, which may be an invaluable tool in unraveling the mechanisms of SNS-related diseases.

Stimulation of Sympathetic Nerve Using Ultraflexible Cuff Electrodes Inhibits Inflammation Caused by Tendon Rupture

AbstractInflammation is a serious symptom of tendon rupture, that leads to peritendinous adhesion and damages the recovery of motor function. Although it is commonly treated using medical therapy, side effects occur in the cardiovascular and genitourinary systems. Electrical stimulation (ES) is a novel alternative to neural modulation. However, its inflammatory inhibitory effect around the tendon has rarely been investigated. Here, an ultraflexible cuff electrode with a thickness of only 3.3 µm is constructed to conformally wrap around the sympathetic chain ganglia for both stimulation and recording. The superior pliancy of the electrode causes less damage to the surrounding tissues and enhances the efficiency of stimulation and recording. ES reduces inflammation‐related factors of IL‐6 and IL‐1β by 51.6% and 19.8%, respectively, and increases the sympathetic nerve neurotransmitter of norepinephrine (NE) by almost an order of magnitude in the ruptured tendon. Sympathetic recordings have also demonstrated that more neural activity is evoked after ES. To the best of the knowledge, this study is the first to verify that the ES of the sympathetic nerve can inhibit inflammation around the tendon, bringing new inspiration for the tendon rupture treatment.

Norepinephrine induces anoikis resistance in high-grade serous ovarian cancer precursor cells.

High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines were able to survive in ultra-low-attachment (ULA) culture in a β-adrenergic receptor-dependent (β-AR-dependent) manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE were abrogated using the β-AR blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony-stimulating factor 2. These findings provide mechanistic insight and identify targets that may be regulated by ovary-derived NE in early HGSC.

Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases.

In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. Nine participants had low initial myocardial 18F-dopamine-derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) (P = 0.0009 by Fisher's exact test). Conversely, all 9 LBD+ participants had low 18F-dopamine-derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity (P < 0.0001 by Fisher's exact test). Cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not. gov NCT00775853. Division of Intramural Research, NIH, NINDS.

Thymic Innervation Impairment in Experimental Autoimmune Encephalomyelitis

Introduction: The thymus is the primary lymphoid organ responsible for normal T-cell development. Yet, in abnormal metabolic conditions as well as an acute infection, the organ exhibits morphological and cellular alterations. It is well established that the immune system is in a tidy connection and dependent on the central nervous system (CNS), which regulates thymic function by means of innervation and neurotransmitters. Sympathetic innervation leaves the CNS and spreads through thymic tissue, where nerve endings interact directly or indirectly with thymic cells contributing to their maintenance and development. Methods: Herein, we hypothesized that brain damage due to an inflammatory process might elicit alterations upon the thymic-CNS neuroimmune axis, altering not just the sympathetic innervation and neurotransmitter release, but also modifying the thymus microenvironment and T-cell development. We used the well-established multiple sclerosis model of experimental autoimmune encephalomyelitis (EAE), to study putative changes in the thymic neural, lymphoid, and microenvironmental compartments. Results: We showed that along with EAE clinical development, thymus morphology, and cellular compartments are affected, altering the peripheric T-cell population and modifying the retrograde thymic communication toward the CNS. Conclusion: Altogether, our data suggest that the thymic-CNS neuroimmune bidirectional axis is compromised in EAE. This imbalance may contribute to an increased and uncontrolled auto-immune reaction.

Elevated serum neuropeptide Y levels are associated with carotid plaque formation in Chinese adults: a cross-sectional study

BackgroundCarotid plaque (CP) formation is an important consequence of atherosclerosis and leads to significant complications. Levels of neuropeptide Y (NPY), which is a sympathetic neurotransmitter, are elevated in cardiovascular diseases. It also has important roles in inflammatory conditions. This study aimed to explore the relationship between serum NPY and CP and to study further the influence of NPY and inflammatory factors on CP.MethodsThis cross-sectional study was conducted among 300 adults who underwent a health examination at the Second Affiliated Hospital of Fujian Medical University in Fujian Province, of whom 177 were finally enrolled. The participants were divided into the CP (n = 120) and non-CP (NCP) or control (n = 57) groups according to the results of carotid artery color Doppler ultrasound. The CP group was further classified into stable plaque (SP, n = 80) and vulnerable plaque (VP, n = 40) groups based on plaque characteristics. Serum NPY and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) levels were examined. Univariate and correlation analyses were used to evaluate the correlation between serum NPY levels, pro-inflammatory cytokines, and the CP phenotype.ResultsThe serum NPY and TNF-α levels of patients in the CP group were significantly higher than those in individuals from the NCP group [ (177.30 ± 43.29) pg.mL− 1 vs. (121.53 ± 40.16)pg.mL− 1, P < 0.001; (41.94 ± 14.19) pg.mL− 1 vs.(33.54 ± 13.37)pg.mL− 1, P = 0.003]. The serum NPY levels of the patients in the VP group were significantly higher than those in patients from the SP group [(191.67 ± 39.87)ng.L− 1 vs.(170.12 ± 43.37)ng.L− 1, P = 0.01, P < 0.05]. Serum TNF-α and NPY levels were positively correlated among patients from the CP group (r = 0.184, P = 0.044). The binary logistic regression analysis showed that serum NPY and TNF-α were independent influencing factors of CP [(OR = 1.029, P < 0.001);(OR = 1.030, P = 0.023)]. The area under the ROC curve of NPY predicting the CP showed statistical significance at a value of 0.819.ConclusionTogether, elevated serum NPY levels seem to be associated with the occurrence of coronary atherosclerosis in Chinese adults.

Sympathetic Neurotransmitter, VIP, Delays Intervertebral Disc Degeneration via FGF18/FGFR2-Mediated Activation of Akt Signaling Pathway.

Neuromodulation-related intervertebral disc degeneration (IVDD) is a novel IVDD pattern and are proposed recently. However, the mechanistic basis of neuromodulation and intervertebral disc (IVD) homeostasis remains unclear. Here, this study aimed to investigate the expression of postganglionic sympathetic nerve fiber-derived vasoactive intestinal peptide (VIP) system in human IVD tissue, and to assess the role of VIP-related neuromodulation in IVDD. Patient samples and in vitro cell experiments showed that the expression of receptors for VIP is negatively correlated with the severity of IVDD, and the administration of exogenous VIP can ameliorate interleukin 1β-induced nucleus pulposus (NP) cell apoptosis and inflammation. Further mRNA-seq analysis revealed that fibroblast growth factor 18- (FGF18)-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway is involved in the protective effects of VIP on inflammation-induced NP cell degeneration. Further analysis identified VIP via its receptor vasoactive intestinal peptide receptor 2 can directly result in decreased expression of miR-15a-5p, which targeted FGF18. Finally, in vivo mice lumbar IVDD model confirmed that focally exogenous administration of VIP can effectively ameliorated the progression of IVDD, as shown by the radiological and histological analysis. In conclusion, these results indicated that sympathetic neurotransmitter, VIP, delayed IVDD via FGF18/FGFR2-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway, which will broaden the horizon concerning how the neuromodulation correlates with IVDD and shed new light on novel therapeutical alternatives to IVDD.

Polycystic Ovary Syndrome Fuels Cardiovascular Inflammation and Aggravates Ischemic Cardiac Injury.

Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear. Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models. Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C+ monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C+ monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14++CD16- monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional Vcam1 silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI. Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.

Sympathetic neurotransmission does not directly cause T-lymphocyte inflammation during psychological trauma

Sympathetic neurotransmission does not directly cause T-lymphocyte inflammation during psychological trauma

Beyond the urothelium: Interplay between autonomic nervous system and bladder inflammation in urinary tract infection, bladder pain syndrome with interstitial cystitis and neurogenic lower urinary tract dysfunction in spinal cord injury-ICI-RS 2023.

Inflammation and neuronal hypersensitivity are reactive protective mechanisms after urothelial injury. In lower urinary tract dysfunctions (LUTD), such as urinary tract infection (UTI), bladder pain syndrome with interstitial cystitis (BPS/IC) and neurogenic LUTD after spinal cord injury (SCI), chronic inflammation can develop. It is unclear how the protective reactionary inflammation escalates into chronic disease in some patients. During its 2023 meeting in Bristol, the International Consultation on Incontinence-Research Society (ICI-RS) reviewed the urothelial and inflammatory changes after UTI, BPS/IC and SCI. Potential factors contributing to the evolution into chronic disease were explored in a think-tank. Five topics were discussed. (1) Visceral fat metabolism participates in the systemic pro-inflammatory effect of noradrenalin in BPS/IC and SCI. Sympathetic nervous system-adipocyte-bladder crosstalk needs further investigation. (2) Sympathetic hyperactivity also potentiates immune depression in SCI and needs to be investigated in BPS/IC. Gabapentin and tumor necrosis factor-α are promising research targets. (3) The exact peripheral neurons involved in the integrative protective unit formed by nervous and immune systems need to be further identified. (4) Neurotransmitter changes in SCI and BPS/IC: Neurotransmitter crosstalk needs to be considered in identifying new therapeutic targets. (5) The change from eubiosis to dysbiosis in SCI can contribute to UTI susceptibility and needs to be unraveled. The think-tank discussed whether visceral fat metabolism, immune depression through sympathetic hyperactivity, peripheral nerves and neurotransmitter crosstalk, and the change in microbiome could provide explanations in the heterogenic development of chronic inflammation in LUTD. High-priority research questions were identified.