The β2-adrenergic receptor controls inflammation by driving rapid IL-10 secretion
Open accessAbstract
The mammalian nervous system communicates important information about the environment to the immune system, but the underlying mechanisms are largely unknown. Secondary lymphoid organs are highly innervated by sympathetic neurons that secrete norepinephrine (NE) as the primary neurotransmitter. Immune cells express adrenergic receptors, enabling the sympathetic nervous system to directly control immune function. NE is a potent immunosuppressive factor and markedly inhibits TNF-α secretion from innate cells in response to lipopolysaccharide (LPS). In this study, we demonstrate that NE blocks the secretion of a variety of proinflammatory cytokines by rapidly inducing IL-10 secretion from innate cells in response to multiple Toll-like receptor (TLR) signals. NE mediated these effects exclusively through the β2-adrenergic receptor (ADRB2). Consequently, Adrb2-/- animals were more susceptible to L. monocytogenes infection and to intestinal inflammation in a dextran sodium sulfate (DSS) model of colitis. Further, Adrb2-/- animals rapidly succumbed to endotoxemia in response to a sub-lethal LPS challenge and exhibited elevated serum levels of TNF-α and reduced IL-10. LPS-mediated lethality in WT animals was rescued by administering a β 2-specific agonist and in Adrb2-/- animals by exogenous IL-10. These findings reveal a critical role for ADRB2 signaling in controlling inflammation through the rapid induction of IL-10. Our findings provide a fundamental insight into how the sympathetic nervous system controls a critical facet of immune function through ADRB2 signaling.
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Signaling on ADRB2 in immune cells has largely been shown to be anti-inflammatory.
“While signaling on ADRB2 in immune cells has largely been shown to be anti-inflammatory (Agac et al., 2018; Nance and Sanders, 2007), our study suggests that ADRB3 activation after acute stress exposure may be detrimental for adaptation to a subsequent inflammatory challenge.”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Agac et al., 2018
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- Authors
- Ağaç, D., Estrada, L. D., Maples, R., Hooper, L. V., & Farrar, J. D.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Farrar, J. David
- Venue
- Brain Behavior and Immunity
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 74
- Pages
- 176-185
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC6289674
- OpenAlex
- W2889788554
- Cited by
- 200
- References
- 74
- Citations by year
- 2026: 24 · 2025: 26 · 2024: 22 · 2023: 26 · 2022: 31 · 2021: 31 · 2020: 25 · 2019: 15
- FWCI
- 7.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Brain Behavior and Immunity (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01AI56222, R56AI125545)
- American Association of Immunologists (T32AI005284, T32GM008203)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- beta2-adrenergic receptor, IL-10 secretion, norepinephrine, sympathetic nervous system, Toll-like receptor signaling, endotoxemia, lipopolysaccharide, Listeria monocytogenes infection, colitis, TNF-α, innate immune cells, beta-adrenergic agonists, neuroimmune interactions
- MeSH terms
- Animals, Immune System, Inflammation, Lipopolysaccharides, Mice, Inbred BALB C, Mice, Inbred C57BL, Norepinephrine, Sympathetic Nervous System, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Cytokines, Interleukin-10, Receptors, Adrenergic, beta-2, Toll-Like Receptors, Mice
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