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6-Hydroxydopamine promotes antitumor immunity through macrophage remodeling beyond sympathetic ablation

ABSTRACT: Chronic stress activates the sympathetic nervous system (SNS) and has been linked to cancer progression, yet the role of SNS in cancer remains controversial. To investigate sympathetic regulation of cancer, we use genetic, pharmacological (6-hydroxydopamine, 6-OHDA) and surgical sympathetic ablation in a transgenic mouse model of breast cancer. Although all methods effectively deplete sympathetic nerves, only 6-OHDA, a neurotoxin targeting catecholaminergic neurons, suppresses tumor growth. Mechanistically, 6-OHDA promotes monocyte recruitment and their differentiation into pro-inflammatory CD64⁺Sca-1⁺ macrophages (MoMacs) through type I interferon signaling. These MoMacs function as antigen-presenting cells, stimulating type 1 T helper (TH1) cells to combat tumor growth. Depletion of MoMacs abolishes both TH1 response and 6-OHDA’s tumor-suppressive effect. Conversely, genetic sympathectomy fail to alter immune infiltration, distinguishing 6-OHDA's immune-modulatory effect from sympathetic ablation. Our findings reveal an unexpected off-target effect of 6-OHDA that suppresses tumor growth by modulating the immune microenvironment, which is independent of sympathetic ablation.

ORGANISM(S): Mus musculus

PROVIDER: GSE305030 | GEO | 2026/03/18

REPOSITORIES: GEO

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Sympathetic nervous tone limits the development of myeloid-derived suppressor cell

Project description:Sympathetic nerves that innervate lymphoid organs regulate immune development and function by releasing norepinephrine (NE) that is sensed by immune cells via their expression of adrenergic receptors (ARs). Here, we demonstrate that ablation of SNS signaling suppresses tumor immunity, and we dissect the mechanism of such immune suppression. We report that disruption of the SNS in mice removes a critical α-adrenergic signal required for maturation of myeloid cells in normal as well as tumor-bearing mice. In tumor-bearing mice, disruption of the α-adrenergic signal leads to the accumulation of immature myeloid-derived suppressor cells (MDSC) that suppress tumor immunity and promote tumor growth. Furthermore, we show that these SNS-responsive MDSCs drive expansion of regulatory T cells via secretion of the alarmin heterodimer S100A8/A9, thereby compounding their immunosuppressive activity. Our results describe a regulatory framework in which sympathetic tone controls the development of innate and adaptive immune cells and influences their activity in health and disease.

2020-09-01 | GSE154973 | GEO

Proteomic Data of Orthotopic Renal RENCA Cell Xenografts in Balb/c Mice After Sympathetic Nerve Ablation with 6-OHDA and of the Control Group

Project description:Proteomic Data of Orthotopic Renal RENCA Cell Xenografts in Balb/c Mice After Sympathetic Nerve Ablation with 6-OHDA and of the Control Group

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Activation of sympathetic nervous system drives dry eye onset via norepinephrine-β2-adrenergic receptor signaling in mice

Project description:Dry eye disease (DED) and sympathetic nervous system (SNS) activation have clear association with chronic environmental and psychogenic stress. However, the relationship and mechanism of SNS activation in dry eye pathogenesis remains elusive. Here we first found that the DED mice induced by chronic desiccating stress and scopolamine exhibited the SNS activation and elevated corneal norepinephrine (NE) contents. However, systemic SNS ablation with 6-OHDA and local NE depletion with DSP-4 treatment markedly alleviated the dry eye severity. More directly, topical application of NE phenocopied the dry eye syndrome in healthy mice, but not in mice with Adrb2 gene knockout, the dominant adrenergic receptor in cornea. In contrast, topical administration of selective Adrb2 antagonist ICI 118551 significantly attenuated the dry eye severity, including the increased tear secretion, improved corneal epithelial barrier function, and the reduced expressions of matrix-metalloproteinases, chemokines and inflammatory cytokines. Transcriptomic analysis and experimental validations underscored the strong links of top 10 downregulated pathways and dry eye-related inflammatory and immune responses, including TNF, NF-κB, chemokines and IL-17 signaling. Taken together, these results provide direct evidence of SNS activation in driving dry eye onset through NA-Adrb2 signaling pathway, which offers potential preventative and therapeutic approach for dry eye diseases.

2026-02-04 | GSE288681 | GEO

The innate thermogenic capacity of brown adipose tissue develops independently of sympathetic signaling

Project description:Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.

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Sympathectomy effect on muscle clock

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Sympathetic inputs regulate adaptive thermogenesis in brown adipose tissue through cAMP-Salt inducible kinase axis

Project description:Various physiological stimuli, such as cold environment, diet, and hormones, trigger brown adipose tissue (BAT) to produce heat through sympathetic nervous system (SNS)- and -adrenergic receptors (ARs). The AR stimulation increases intracellular cAMP levels through heterotrimeric G proteins and adenylate cyclases, but the processes by which cAMP modulates brown adipocyte function are not fully understood. Here we described that specific ablation of cAMP production in brown adipocytes led to reduced lipolysis, mitochondrial biogenesis, uncoupling protein 1 (Ucp1) expression, and consequently defective adaptive thermogenesis. Elevated cAMP signaling by sympathetic activation inhibited Salt-inducible kinase 2 (Sik2) through protein kinase A (PKA)-mediated phosphorylation in brown adipose tissue. Inhibition of SIKs enhanced Ucp1 expression in differentiated brown adipocytes and Sik2 knockout mice exhibited enhanced adaptive thermogenesis at thermoneutrality in an Ucp1-dependent manner. Taken together, our data indicate that suppressing Sik2 by PKA-mediated phosphorylation is a requisite for SNS-induced Ucp1 expression and adaptive thermogenesis in BAT, and targeting Sik2 may present a novel therapeutic strategy to ramp up BAT thermogenic activity in humans.

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Transcription profiling by array of newt midbrain ependymoglia cells after 6-OHDA mediated ablation of midbrain dopamingeric neurons

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Gene expression changes after epinephrine treated in breast cancer tumor cell

Project description:Chronic stress triggers activation of the sympathetic nervous system (SNS) and drives malignancy. Using an immunodeficient murine system, we show that chronic stress promotes breast cancer stem-like properties via lactate dehydrogenase A (LDHA) dependent metabolic rewiring. In this dataset, we used microarray to characterize the mRNA expression profiles from primary PBS and Epinephrine -treated MDA-MB-231 tumor cells.

2019-03-18 | GSE116781 | GEO

A gatekeeper mechanism of the noradrenergic neural control of tear secretion via the NA-Adra1a-Ucp2 pathway

Project description:Tears are mainly secreted from the lacrimal gland under precise controls by autonomic neural response to external sensory and psychogenic emotional stimulation. Dynamic volume and compositional changes of tears may lead to development of dry eye disease. The role of sympathetic nerve system (SNS) in controlling tear secretion and the noradrenergic neural circuit projecting from brain to lacrimal gland remain unexplored. Here, we discovered the dense sympathetic innervation of mouse lacrimal gland and investigated its physiological role in regulating tear production. In response to dry eye stimuli, SNS became overactivated with high noradrenaline (NA) in the lacrimal gland. Using gain- and loss-of-functional approaches, including pharmacologic, surgical, chemogenetic manipulations, and genetic knockout mice of specific adrenergic receptors, we demonstrated that both SNS ablation and NA blockage markedly increased tear volume and alleviated dry eye diseases. Mechanistically, activation of SNS released NA to reduce tear secretion through binding to α1a-adrenergic receptor (Adra1a) that targeted mitochondrial Ucp2 in the acinar and myoepithelial cells of the lacrimal gland. Consequently, antagonization of NA and Ucp2 markedly increased tear secretion. Using a retrograde neuronal tracing technique in combination with physiologic experiments of tear reduction and hypersecretion, we identified a novel noradrenergic neural circuit projecting from the brain locus coeruleus to the lacrimal gland and the orchestrated controlling of parasympathetic and sympathetic nervous system for tear secretion. Together, our data define a novel NA-Adra1a-Ucp2 signaling pathway as a gatekeeper mechanism for controlling tear secretion from the lacrimal gland. These findings provide novel mechanistic insights into sympathetic role in tear secretion and potential therapeutic options for treatment of dry eye disease.

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