Adrenergic inhibition of innate anti-viral response: PKA blockade of Type I interferon gene transcription mediates catecholamine support for HIV-1 replication
Abstract
Type I interferons (IFN-alpha and -beta) play a key role in anti-viral immunity, and we sought to define the molecular mechanisms by which the sympathetic nervous system (SNS) inhibits their effects. In peripheral blood leukocytes and plasmacytoid dendritic cells (pDC2), induction of interferon anti-viral activity by double-stranded RNA (poly-I:C) or CpG DNA was substantially inhibited by norepinephrine and by pharmacologic activation of the cAMP/PKA signaling pathway. This effect was specific to Type I interferons and driven by PKA-mediated repression of IFNA and IFNB gene transcription. Luciferase reporter analyses identified tandem interferon response factor-binding sites in positive regulatory domains I and III of the IFNB promoter as a key target of PKA inhibition. PKA suppression of Type I interferons was associated with impaired transcription of interferon response genes supporting the "anti-viral state", and was sufficient to account for norepinephrine-induced enhancement of HIV-1 replication. Given the ubiquitous role of Type I interferons in containing viral replication, PKA-mediated inhibition of IFN transcription could explain the stimulatory effects of catecholamines on a broad range of viral pathogens.
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SNS activation of the CTRA is mediated in large part by beta-adrenergic receptors, which stimulate transcription factors such as NF-kB, GATA, and CREB to up-regulate proinflammatory genes while inhibiting interferon response factor family transcription factors that control Type I interferon genes.
“SNS activation of the CTRA is mediated in large part by β-adrenergic receptors, which stimulate transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), GATA, and cAMP response element-binding protein (CREB) to selectively up-regulate transcription of proinflammatory genes (e.g., IL6 [19]) while simultaneously inhibiting the activity of transcription”
From Human Social Genomics (2014) · cites this paper as [34]
The sympathetic nervous system allows the CNS to steer innate immune responses between proinflammatory and antiviral phenotypes.
“the SNS allows the CNS to 'steer' innate immune responses between proinflammatory and antiviral phenotypes”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Collado-Hidalgo et al, 2006
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Slavich, G. M., & Irwin, M. R. (2014) · Psychological Bulletin · doi:10.1037/a0035302 · Cited by 2,206 · see citing works
Reciprocal regulation of the neural and innate immune systems
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“In addition to the global anti-inflammatory effect of glucocorticoids, a second neural pathway mediated by the SNS allows the CNS to 'steer' innate immune responses between pro-inflammatory and antiviral programme”
BackgroundSelf-citationSocial regulation of gene expression in human leukocytes
Cole, S. W., Hawkley, L. C., Arevalo, J. M., Sung, C. Y., Rose, R. M., & Cacioppo, J. T. (2007) · Genome Biology · doi:10.1186/gb-2007-8-9-r189 · Cited by 745 · see citing works
“ISGF12 was assayed using published primer sequences and reaction conditions [ 33 ].”
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Cole, S. W., Capitanio, J. P., Chun, K., Arevalo, J. M. G., Ma, J., & Cacioppo, J. T. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1514249112 · Cited by 310 · see citing works
Self-citationCole, S. W., Hawkley, L. C., Arevalo, J. M. G., & Cacioppo, J. T. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014218108 · Cited by 306 · see citing works
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Cognitive-Behavioral Stress Management Reverses Anxiety-Related Leukocyte Transcriptional Dynamics
Antoni, M. H., Lutgendorf, S. K., Blomberg, B., Carver, C. S., Lechner, S., Diaz, A., Stagl, J., Arevalo, J. M. G., & Cole, S. W. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.10.007 · Cited by 251 · see citing works
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Self-citation
- Authors
- Collado-Hidalgo, A., Sung, C., & Cole, S.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Cole, Steve
- ORCID
- Cole, Steve
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 20
- Issue
- 6
- Pages
- 552-563
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W2084120087
- Cited by
- 69
- References
- 114
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 7 · 2012: 4
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (T32MH019925, T32 MH 19925)
- National Institute of Allergy and Infectious Diseases (R01 AI52737, R01AI052737)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- type I interferon, protein kinase A, sympathetic nervous system, norepinephrine, catecholamines, HIV-1 replication, antiviral innate immunity, plasmacytoid dendritic cells, interferon-beta promoter, cAMP signaling, double-stranded RNA, CpG DNA
- MeSH terms
- Autonomic Nervous System, Cells, Cultured, Dendritic Cells, Gene Expression Regulation, Humans, Immunity, Innate, Interferon Type I, Leukocytes, Norepinephrine, Promoter Regions, Genetic, RNA, Double-Stranded, Transcription, Genetic, Virus Replication, Neuroimmunomodulation, Signal Transduction, HIV-1, HIV Infections, Cyclic AMP-Dependent Protein Kinases, CpG Islands
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