Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells
Open accessAbstract
Cross-talk between the sympathetic nervous system (SNS) and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE) in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs) in immune cells activates the cAMP-protein kinase A (PKA) intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune–SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP–PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP–PKA to mitogen-activated protein kinase (MAPK) pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for “signal switching” in immune cells.
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Adrenergic signalling can have both anti-inflammatory and pro-inflammatory effects, depending on adrenergic receptor subtype, level of activation of specific cell types, and stage of disease progression.
“Both anti-inflammatory and pro-inflammatory effects of adrenergic signalling have been demonstrated, depending upon the subtype of adrenergic receptors expressed167, the level of activation of specific cell types and the stage of disease progression168.”
From The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease (2018) · cites this paper as [168]
Persistent activation of the sympathetic nervous system shifts signalling within immune organs and cells towards pro-inflammatory pathways, as observed in hypertension and chronic kidney disease.
“However, persistent activation of the SNS results in changes in signalling within immune organs and cells towards pro-inflammatory pathways168, as observed in hypertension and CKD169,170.”
From The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease (2018) · cites this paper as [168]
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- Authors
- Lorton, D., & Bellinger, D.
- Affiliations
- Kent State University (US)
- Loma Linda University (US)
- Corresponding author
- Lorton, Dianne
- ORCID
- Lorton, Dianne
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2015-03-11
- Volume
- 16
- Issue
- 3
- Pages
- 5635-5665
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC4394497
- OpenAlex
- W1993341098
- Cited by
- 221
- References
- 147
- Citations by year
- 2026: 23 · 2025: 31 · 2024: 26 · 2023: 26 · 2022: 17 · 2021: 17 · 2020: 15 · 2019: 22 · 2018: 14 · 2017: 17 · 2016: 10 · 2015: 3
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- beta2-adrenergic receptor, sympathetic nervous system, norepinephrine, cAMP/PKA signaling, MAPK signaling, signal switching, sympathetic neurons, immune cells, immunosuppression, lymphoid organs
- MeSH terms
- Cell Communication, Humans, Immunity, Innate, Lymphocytes, Receptors, Adrenergic, beta, Sympathetic Nervous System, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Mitogen-Activated Protein Kinases, Receptors, G-Protein-Coupled, Adaptive Immunity
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