Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety
Open accessAbstract
Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety. Here we show that repeated social defeat stress in mice activated threat appraisal centers in the brain that spatially coincided with microglial activation and endothelial facilitation of monocyte recruitment. Moreover, microglial depletion with a CSF1R antagonist prior to stress prevented the recruitment of monocytes to the brain and abrogated the development of anxiety. Cell-specific transcriptional profiling revealed that microglia selectively enhanced CCL2 expression, while monocytes expressed the pro-inflammatory cytokine interleukin-1β (IL-1β). Consistent with these profiles, the recruited inflammatory monocytes with stress adhered to IL-1R1+ neurovascular endothelial cells and this interaction was blocked by microglial depletion. Furthermore, disruption of IL-1β signaling by caspase-1 KO specifically within bone marrow-derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1β. Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1β-producing monocytes, which stimulated brain endothelial IL-1R1. Thus, monocyte IL-1β production represents a novel mechanism that underlies behavioral complications associated with stress-related psychiatric disorders.
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Previous studies report conflicting findings with regard to infiltration of peripheral immune cells into the brain following social stress.
“Previous studies report conflicting findings with regard to infiltration of peripheral immune cells into the brain following social stress14, 34.”
From Social stress induces neurovascular pathology promoting depression (2017) · cites this paper as [34]
The Results section reports that repeated social defeat increased monocyte adhesion to brain endothelial cells, supporting one finding about peripheral immune-cell recruitment after social stress. The paper does not report conflicting findings across studies, and endothelial adhesion does not by itself establish infiltration into brain tissue. No page number is available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMonocytes are recruited to vessels and ventricular space within the brain.
“We nevertheless confirm a recent report showing that monocytes are recruited to vessels and ventricular space within the brain34.”
From Social stress induces neurovascular pathology promoting depression (2017) · cites this paper as [34]
The Results section (‘Threat appraisal during stress promotes microglial activation and monocyte recruitment’; page unavailable) reports that stress increased monocyte adhesion to brain endothelial cells, supporting recruitment to vessels. Our copy does not report recruitment to the ventricular space; searches for ventricular space, ventricles, and choroid plexus found no such passage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIncreased levels of CRP and its proinflammatory activity can drive CNS inflammation through microglia and astrocytes activation.
“Moreover, increased levels of CRP and its proinflammatory activity can drive CNS inflammation through microglia and astrocytes activation [40,41,42].”
From C-Reactive protein as a biomarker for major depressive disorder? (2022) · cites this paper as [41]
Repeated social defeat in mice promotes accumulation of peripheral monocytes in the brain that augment IL-1β signaling and cause prolonged anxiety-like behavior.
“We have reported that repeated social defeat (RSD) in mice promoted the accumulation of peripheral monocytes in the brain that augmented IL-1β signaling and caused prolonged anxiety-like behavior [21, 22].”
From Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety (2019) · cites this paper as [21]
Repeated social defeat induces cell adhesion molecule (ICAM-1, VCAM, E-Selectin) and IL-1 receptor-1 expression on the brain vasculature that provide interaction sites for monocytes recruited from the periphery.
“Repeated social defeat induces cell adhesion molecule (ICAM-1, VCAM, E-Selectin) and IL-1 receptor-1 expression on the brain vasculature that provide interaction sites for monocytes recruited from the periphery [17, 21, 35].”
From Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety (2019) · cites this paper as [21]
Microglia activated during stress produce chemokines to recruit IL-1β-expressing monocytes that propagate IL-1 signaling into the brain via the vascular endothelium.
“Microglia activated during stress produce chemokines to recruit IL-1β-expressing monocytes that propagate IL-1 signaling into the brain via the vascular endothelium [21].”
From Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety (2019) · cites this paper as [21]
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References 43 · Cited by 365
- Authors
- McKim, D. B., Weber, M. D., Niraula, A., Sawicki, C. M., Liu, X., Jarrett, B. L., Ramirez-Chan, K., Wang, Y., Roeth, R. M., Sucaldito, A. D., Sobol, C. G., Quan, N., Sheridan, J. F., & Godbout, J. P.
- Affiliations
- The Ohio State University Wexner Medical Center (US)
- The Ohio State University (US)
- Corresponding author
- Sheridan, J F
- Godbout, J P
- Venue
- Molecular Psychiatry
- Published
- 2017-04-04
- Volume
- 23
- Issue
- 6
- Pages
- 1421-1431
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5628107
- OpenAlex
- W2605062075
- Cited by
- 365
- References
- 43
- Citations by year
- 2026: 27 · 2025: 30 · 2024: 34 · 2023: 61 · 2022: 49 · 2021: 40 · 2020: 42 · 2019: 37 · 2018: 37 · 2017: 8
- FWCI
- 16.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.nature.com
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Americanae (AECID Library) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Funders
- Ohio State University
- Plexxikon
- National Institutes of Health
- National Institute on Aging (R01AG051902)
- National Institute of Mental Health (R01MH097243, R01MH109165, F31MH109234, R01MH093473)
- National Institute of Dental and Craniofacial Research (F30DE026075, T32DE014320)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- social defeat stress, anxiety, microglia, inflammatory monocytes, IL-1β, IL-1 receptor 1, brain endothelium, neuroinflammation, CSF1R, MCP-1, caspase-1, bone marrow-derived cells, threat appraisal, stress-related psychiatric disorders
- MeSH terms
- Animals, Anxiety, Anxiety Disorders, Brain, Endothelium, Male, Mice, Inbred C57BL, Monocytes, Stress, Psychological, Signal Transduction, Cytokines, Microglia, Endothelial Cells, Mice, Interleukin-1beta
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