Effect of isoproterenol on RAW264.7 in vitro
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE274725 | GEO | 2025/04/30
REPOSITORIES: GEO
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Project description:BACKGROUND Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. METHODS Sox10iCreERT2/Rpl22HA/+ mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH+ sympathetic neurons and glial-restricted Sox10iCreERT2/JellyOPfl/+/Rpl22HA/+ mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. RESULTS With ~4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glia reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. CONCLUSIONS Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development.
2023-11-15 | GSE198889 | GEO
Project description:The sympathetic nervous system (SNS) plays a central role in blood pressure regulation. Recent studies have shown that cells of the distal convoluted tubule (DCT) can be stimulated directly via the beta-adrenergic receptor resulting in activation of the NaCl cotransporter NCC. Whether these effects are mediated by the beta1- or beta2-adrenergic receptor is unclear, and the acute signaling cascades rapidly activated by beta-adrenergic receptor stimulation in the DCT are unknown. Here in this study, we aim to identify the rapid salbutamol-mediated (beta2-adrenergic receptor) signaling in the DCT by looking at global protein phosphorylation changes in the mpkDCT cells.
2021-05-17 | PXD019051 | Pride
Project description:Exposure to cold temperatures is known to mimic the effects of exercise, protecting against obesity and improving metabolic health. Cold is known to act through the sympathetic nervous systems and -adrenergic signaling, but here we report that cold temperature can directly activate a variety of gene programs in muscle independent of -adrenergic signaling.
2018-08-16 | E-MTAB-4528 | biostudies-arrayexpress
Project description:Activation of the sympathetic nervous system causes pronounced metabolic changes that are mediated by multiple adrenergic receptor subtypes. Systemic treatment with β<sub>2-</sub>adrenergic receptor agonists results in multiple beneficial metabolic effects, including improved glucose homeostasis. To elucidate the underlying cellular and molecular mechanisms, we chronically treated wild-type mice and several newly developed mutant mouse strains with clenbuterol, a selective β<sub>2</sub>-adrenergic receptor agonist. Clenbuterol administration caused pronounced improvements in glucose homeostasis and prevented the metabolic deficits in mouse models of β-cell dysfunction and insulin resistance. Studies with skeletal muscle-specific mutant mice demonstrated that these metabolic improvements required activation of skeletal muscle β<sub>2</sub>-adrenergic receptors and the stimulatory G protein, G<sub>s</sub>. Unbiased transcriptomic and metabolomic analyses showed that chronic β<sub>2</sub>-adrenergic receptor stimulation caused metabolic reprogramming of skeletal muscle characterized by enhanced glucose utilization. These findings strongly suggest that agents targeting skeletal muscle metabolism by modulating β<sub>2</sub>-adrenergic receptor-dependent signaling pathways may prove beneficial as antidiabetic drugs.
2022-08-26 | MTBLS467 | MetaboLights
Project description:Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac b-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.
2021-08-09 | GSE181674 | GEO
Project description:Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes. Cold is known to act indirectly through the sympathetic nervous systems and -adrenergic signaling, but here we report that cold temperature can directly activate a thermogenic gene program in adipocytes independent of -adrenergic signaling.
2018-08-16 | E-MTAB-4526 | biostudies-arrayexpress
Project description:We recently identified pathogenic KIF1Bb mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1Bb in the mouse sympathetic nervous system based on a cre recombination system driven by the dopamine beta hydroxylase (DBH) promoter. We observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation in KIF1Bb deficient sympathetic ganglia.
2017-08-30 | GSE90952 | GEO
Project description:Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. Despite decades of investigations, predominantly focusing on ryanodine receptor and phospholamban phosphorylation, the molecular mechanisms underlying the sympathetic nervous system control of cardiac contractility remain controversial and incompletely elucidated. Here, we identify the calcium-channel inhibitor Rad as a critical component. In cardiomyocytes isolated from knock-in mice expressing Rad with alanine-substitutions of the four PKA-phosphorylated serine residues (4SA-Rad), calcium currents cannot be increased by adrenergic agonists or phosphatase inhibitor. In these mice, basal cardiac contractility, exercise capacity and heart rate are reduced, and the augmentation of contractile force by adrenergic agonists is severely blunted. Expression of mutant calcium-channel β-subunits that cannot bind Rad is sufficient to restore calcium influx and cardiac contractility in 4SA-Rad mice to levels induced by adrenergic agonists in wild-type mice, revealing a potential therapeutic approach to enhance cardiac contractility while bypassing stimulation of adrenergic receptors.
2022-09-26 | PXD033492 | Pride
Project description:Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system plays a pivotal role in regulating immune system and skeleton, however, the impact of TBI on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. Importantly, the adrenergic hypersensitivity swiftly skews bone marrow hematopoietic lineage cells toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptors (ARs) eliminate TBI mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. Moreover, β3- and β2-ARs agonists synergistically promote M2 macrophages infiltration in callus and accelerate bone healing process. Our results suggest that TBI shapes the anti-inflammation environment during early stage of fracture healing, implicating the sympathetic nerve system as a potential target that can be exploited to treat fracture.
2023-04-12 | GSE229258 | GEO
Project description:The autonomic nervous system (ANS) is a regulator of major pathological events in the tumor microenvironment (TME) of solid carcinomas where the branches of ANS have antagonistic effects on tumor growth and metastasis. Neural activity recorded from breast tumors may be associated with autonomic system function. To test this hypothesis, we performed in vivo chronic electrical recordings from murine mammary tumors of triple negative breast cancers (TNBC) following complete sub-diaphragmatic vagotomy and chemical sympathectomy. In addition to TNBC mammary tumors, we also obtained daily electrical recordings from mammary tumors overexpressing human epidermal growth factor receptor-2 (HER2) following chemical sympathectomy. Our results show that tumoral neural activity is partially blocked in vagotomized animals while it is completely absent in the sympathectomized subjects. These studies indicate that neural activity in TNBC and HER2+ tumors is predominantly generated by peripheral nor-adrenergic sympathetic nerves and provide evidence of a strong active link between the brain and tumor through the autonomic nervous system. The results implicate a new and as yet unexplored mechanism to investigate the potential role of the sympathetic nervous system in the regulation of tumor growth and metastasis.
2024-02-05 | GSE254740 | GEO