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Sympathetic Release of Splenic Monocytes Promotes Recurring Anxiety Following Repeated Social Defeat
Open accessAbstract
Background Neuroinflammatory signaling may contribute to the pathophysiology of chronic anxiety disorders. Previous work showed that repeated social defeat (RSD) in mice promoted stress-sensitization that was characterized by the recurrence of anxiety following subthreshold stress 24 days after RSD. Furthermore, splenectomy following RSD prevented the recurrence of anxiety in stress-sensitized mice. We hypothesize that the spleen of RSD-exposed mice became a reservoir of primed monocytes that were released following neuroendocrine activation by subthreshold stress.Methods Mice were subjected to subthreshold stress (i.e., single cycle of social defeat) 24 days after RSD, and immune and behavioral measures were taken.Results Subthreshold stress 24 days after RSD re-established anxiety-like behavior that was associated with egress of Ly6C(hi) monocytes from the spleen. Moreover, splenectomy before RSD blocked monocyte trafficking to the brain and prevented anxiety-like behavior following subthreshold stress. Splenectomy, however, had no effect on monocyte accumulation or anxiety when determined 14 hours after RSD. In addition, splenocytes cultured 24 days after RSD exhibited a primed inflammatory phenotype. Peripheral sympathetic inhibition before subthreshold stress blocked monocyte trafficking from the spleen to the brain and prevented the re-establishment of anxiety in RSD-sensitized mice. Last, β-adrenergic antagonism also prevented splenic monocyte egress after acute stress.Conclusions The spleen served as a unique reservoir of primed monocytes that were readily released following sympathetic activation by subthreshold stress that promoted the re-establishment of anxiety. Collectively, the long-term storage of primed monocytes in the spleen may have a profound influence on recurring anxiety disorders.
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“In fact, RSD significantly decreases B-cell and T-cell lymphocytes in the BM and circulation (Engler et al, 2004;McKim et al, 2015), thereby shifting hematopoiesis to produce myeloid lineage cells.”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as McKim et al, 2015
In the citing paper
“However, reexposure to a single cycle of social defeat 24 days after RSD reactivated the neuroimmune axis, leading to increased monocyte trafficking to the brain and elevated proinflammatory cytokine signaling (Wohleb et al, 2014a;McKim et al, 2015).”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as McKim et al, 2015
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“Support for the role of spleen-derived monocytes to influence the inflammatory state of resident microglia comes from the finding that splenectomy attenuated microglial cytokine expression (Wohleb et al, 2014a;McKim et al, 2015).”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as McKim et al, 2015
In the citing paper
“Similar to the egress of monocytes from the BM after RSD, differentiation and release of splenic monocytes following stress reexposure is likely mediated by noradrenergic signaling via circulating or direct sympathetic nervous system innervation of the spleen (McKim et al, 2015).”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as McKim et al, 2015
In the citing paper
“Interestingly, trafficking of peripheral monocytes to the brain was not primarily driven by monocyte production and egress from the BM, such as what occurs following initial exposure to RSD.Instead, reexposure to subthreshold stress caused the release of primed monocytes from a splenic monocyte reservoir (Wohleb et al, 2014a;McKim et al, 2015).”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as McKim et al, 2015
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BackgroundSubpopulations of Mouse Blood Monocytes Differ in Maturation Stage and Inflammatory Response
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Myocardial infarction accelerates atherosclerosis
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Integrating neuroimmune systems in the neurobiology of depression
Wohleb, E. S., Franklin, T., Iwata, M., & Duman, R. S. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.69 · Cited by 668
Self-citationLoneliness, Social Isolation, and Cardiovascular Health
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Metadata
- Authors
- McKim, D. B., Patterson, J. M., Wohleb, E. S., Jarrett, B. L., Reader, B. F., Godbout, J. P., & Sheridan, J. F.
- Affiliations
- The Ohio State University (US)
- Yale University (US)
- Corresponding author
- Sheridan, John F.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 79
- Issue
- 10
- Pages
- 803-813
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4728074
- OpenAlex
- W1600219138
- Cited by
- 137
- References
- 50
- Citations by year
- 2026: 8 · 2025: 3 · 2024: 15 · 2023: 19 · 2022: 19 · 2021: 11 · 2020: 10 · 2019: 10 · 2018: 13 · 2017: 17 · 2016: 11
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (NIMH) (R01-MH093473, R01-MH097243)
- National Institute of Dental and Craniofacial Research Training (T32-DE014320)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- repeated social defeat, splenic monocytes, neuroinflammation, sympathetic nervous system, splenectomy, stress sensitization, beta-adrenoceptor antagonism, Ly6Chi monocytes
- MeSH terms
- Animals, Anxiety, Brain, Cell Movement, Disease Models, Animal, Dominance-Subordination, Guanethidine, Male, Mice, Inbred C57BL, Monocytes, Spleen, Splenectomy, Stress, Psychological, Sympathetic Nervous System, Sympatholytics, Neuroimmunomodulation, Cohort Studies
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