Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior
Open accessAbstract
Major depressive disorder (MDD) is one of the most common and debilitating neuropsychiatric illnesses. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of MDD. The complement system represents one of the major effector mechanisms of the innate immune system, and plays a critical role in inflammation. However, the role of complement components in MDD is not well understood. Here, we found significant increase in component 3 (C3) expression in the prefrontal cortex (PFC) of depressed suicide subjects. We tested the role of altered C3 expression in mouse model of depression and found that increased C3 expression in PFC as a result of chronic stress causes depressive-like behavior. Conversely, mice lacking C3 were resilient to stress-induced depressive-like behavior. Moreover, selective overexpression of C3 in PFC was sufficient to cause depressive-like behavior in mice. We found that C3a (activated product of C3) receptor, C3aR+ monocytes were infiltrated into PFC following chronic stress. However, C3aR knockout mice displayed significantly reduced monocyte recruitment into PFC and reduced levels of the proinflammatory cytokine IL-1β in PFC after chronic stress. In addition, C3aR knockout mice did not exhibit chronic stress-induced behavior despair. Similarly, chronic stress-induced increases in C3aR+ monocytes and IL-1β in PFC, and depressive-like behavior were attenuated by myeloid cell depletion. These postmortem and preclinical studies identify C3aR signaling as a key factor in MDD pathophysiology.
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CSDS promotes recruitment of circulating monocytes and macrophages into the brain perivascular space via complement 3 receptor and CX3C chemokine receptor 1 signaling.
“CSDS promotes recruitment of circulating monocytes and macrophages into the brain perivascular space via complement 3 receptor and CX3C chemokine receptor 1 signaling [181–183].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [183]
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- Authors
- Crider, A., Feng, T., Pandya, C. D., Davis, T., Nair, A., Ahmed, A. O., Baban, B., Turecki, G., & Pillai, A.
- Affiliations
- Augusta University (US)
- Nirma University (IN)
- Weill Cornell Medicine (US)
- Douglas Mental Health University Institute (CA)
- Corresponding author
- Pillai, Anilkumar
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 70
- Pages
- 246-256
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5967612
- OpenAlex
- W2789312859
- Cited by
- 112
- References
- 61
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 27 · 2023: 13 · 2022: 16 · 2021: 13 · 2020: 10 · 2019: 8
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Brain Behavior and Immunity (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01 MH 097060)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- C3aR, major depressive disorder, chronic stress, depression-like behavior, monocyte infiltration, prefrontal cortex, IL-1β, neuroinflammation, innate immunity, myeloid cell depletion, suicide, stress resilience
- MeSH terms
- Animals, Autopsy, Depression, Depressive Disorder, Major, Major Depressive Disorder, Disease Models, Animal, Humans, Inflammation, Male, Mice, Inbred C57BL, Monocytes, Receptors, Complement, Stress, Psychological, Signal Transduction, Complement C3a, Cytokines, Prefrontal Cortex, Mice, Knockout, Mice, Interleukin-1beta
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