Dataset Information

Loss of the Sympathetic Signal Produces Sterile Inflammation of the Prostate.

ABSTRACT: Neural innervations exert essential roles in the prostate. However, spatial distribution and regulatory function of such neural inputs are incompletely characterized. Here, we exploited the advanced whole-tissue immunolabeling and optical clearing technique to assess the 3D anatomy of autonomic innervations in the mouse and human prostate for the first time. We observed that sympathetic and parasympathetic inputs in the mouse prostate remained unaffected during castration-induced tissue regression. However, the pharmacologic destruction of sympathetic innervations in the mouse prostate led to sterile inflammation of the tissue, mimicking the disease condition of chronic non-bacterial prostatitis. Also, the genetic ablation of sympathetic inputs produced a similar inflammatory response. Furthermore, we showed that treatment of the specific β2-adrenergic receptor agonists could effectively mitigate the prostate inflammation caused by such sympathetic loss. Together, these results have elucidated the new immunomodulatory function of the sympathetic signal via the β2-adrenergic receptor in prostate inflammatory disease.

SUBMITTER: Hu H

PROVIDER: S-EPMC9127543 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Loss of the Sympathetic Signal Produces Sterile Inflammation of the Prostate.

Hu Hao H Cui Yiwen Y Yang Jing J Cao Ying Y

Frontiers in molecular neuroscience 20220510

Neural innervations exert essential roles in the prostate. However, spatial distribution and regulatory function of such neural inputs are incompletely characterized. Here, we exploited the advanced whole-tissue immunolabeling and optical clearing technique to assess the 3D anatomy of autonomic innervations in the mouse and human prostate for the first time. We observed that sympathetic and parasympathetic inputs in the mouse prostate remained unaffected during castration-induced tissue regressi ...[more]

PMID: 35620446

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Project description:ImportanceRandomized clinical trials are conducted to establish both drug safety and efficacy. However, evidence of adverse events associated with these drugs in the clinical practice setting can be of value at generating hypotheses regarding less common safety issues, even if causality cannot be determined.ObjectiveTo present and analyze cases of intraocular inflammation associated with faricimab therapy in patients referred to a single European institution.Design, setting, and participantsThis was a review starting in April of 2024 of an observational case series. Patients were from a single academic-based tertiary referral center in Switzerland. Included in the analysis were patients referred for intraocular inflammation soon after receiving a faricimab intravitreal injection between June 1, 2022, and March 5, 2024.ExposureFaricimab, 6 mg (0.05 mL of a 120-mg/mL solution), administrated for neovascular age-related macular degeneration or diabetic macular edema.Main outcomes and measuresThe systemic and ocular histories and imaging data available were reviewed. The following were evaluated: visual acuity measured with habitual correction using the Early Treatment of Diabetic Retinopathy Study charts before and after the event; intraocular pressure; patient symptoms; anterior, intermediate, or posterior location of the intraocular inflammation; and the presence of retinal vasculitis. Multimodal imaging including color fundus photographs, fluorescein angiograms, indocyanine green angiograms, and optical coherence tomography were reviewed.ResultsA total of 12 eyes from 7 patients (mean [SD] age, 73.3 [16.7] years; 4 female [57.1%]) over 22 months were identified as having noninfectious intraocular inflammation after intravitreal faricimab injections. Among these cases, in 2 eyes, retinal vasculitis was present together with anterior and posterior inflammation. One of the 2 eyes had an occlusive form of vasculitis of the arteries and veins, leading to subsequent macular capillary nonperfusion and clinically relevant irreversible vision deterioration from 20/80 to 20/2000. The remaining eyes were characterized by moderate anterior segment inflammation without substantial vision changes. The intraocular inflammation event occurred after a median (IQR) of 3.5 (2.0-4.3) faricimab injections. The median (IQR) interval between the last faricimab injection and the diagnosis of inflammation was 28 (24-38) days. Increased intraocular pressure of 30 mm Hg or higher was found in 3 eyes.Conclusions and relevanceThis case series highlights the occurrence of rare, but potentially severe, intraocular inflammation associated with faricimab therapy. Although these findings do not prove causality and can only generate hypotheses for future investigations, these results suggest the importance of continuous surveillance and monitoring for patients undergoing faricimab therapy to promptly identify and manage potential adverse events.

Project description:Background & aimsThe colon is innervated by intrinsic and extrinsic neurons that coordinate functions necessary for digestive health. Sympathetic input suppresses colon motility by acting on intrinsic myenteric neurons, but the extent of sympathetic-induced changes on large-scale network activity in myenteric circuits has not been determined. Compounding the complexity of sympathetic function, there is evidence that sympathetic transmitters can regulate activity in non-neuronal cells (such as enteric glia and innate immune cells).MethodsWe performed anatomical tracing, immunohistochemistry, optogenetic (GCaMP calcium imaging, channelrhodopsin), and colon motility studies in mice and single-cell RNA sequencing in human colon to investigate how sympathetic postganglionic neurons modulate colon function.ResultsIndividual neurons in each sympathetic prevertebral ganglion innervated the proximal or distal colon, with processes closely opposed to multiple cell types. Calcium imaging in semi-intact mouse colon preparations revealed changes in spontaneous and evoked neural activity, as well as activation of non-neuronal cells, induced by sympathetic nerve stimulation. The overall pattern of response to sympathetic stimulation was unique to the proximal or distal colon. Region-specific changes in cellular activity correlated with motility patterns produced by electrical and optogenetic stimulation of sympathetic pathways. Pharmacology experiments (mouse) and RNA sequencing (human) indicated that appropriate receptors were expressed on different cell types to account for the responses to sympathetic stimulation. Regional differences in expression of α-1 adrenoceptors in human colon emphasize the translational relevance of our mouse findings.ConclusionsSympathetic neurons differentially regulate activity of neurons and non-neuronal cells in proximal and distal colon to promote distinct changes in motility patterns, likely reflecting the distinct roles played by these 2 regions.

Dataset Information

Loss of the Sympathetic Signal Produces Sterile Inflammation of the Prostate.

Publications

Loss of the Sympathetic Signal Produces Sterile Inflammation of the Prostate.

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