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Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway

Abstract

Chronic stress is a major risk factor in the pathophysiology of many neuropsychiatric disorders. Further, chronic stress conditions can promote neuroinflammation and inflammatory responses in both humans and animal models. Type I interferons (IFN-I) are critical mediators of the inflammatory response in the periphery and responsible for the altered mood and behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of IFN-I signaling in chronic stress-induced changes in neuroinflammation and behavior. Using the chronic restraint stress model, we found that chronic stress induces a significant increase in serum IFNβ levels in mice, and systemic blockade of IFN-I signaling attenuated chronic stress-induced infiltration of macrophages into prefrontal cortex and behavioral abnormalities. Furthermore, complement component 3 (C3) mediates systemic IFNβ-induced changes in neuroinflammation and behavior. Also, we found significant increases in the mRNA expression levels of IFN-I stimulated genes in the prefrontal cortex of depressed suicide subjects and significant correlation with C3 and inflammatory markers. Together, these findings from animal and human postmortem brain studies identify a crucial role of C3 in IFN-I-mediated changes in neuroinflammation and behavior under chronic stress conditions.

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Fig. 1: IFNAR antibody treatment attenuates chronic stress-induced deficits in social behavior and spatial working memory.
Fig. 2: IFNAR antibody treatment attenuates chronic stress-induced infiltration of macrophages and increases in IFN-I-stimulated gene in the PFC.
Fig. 3: IFNAR antibody treatment attenuates chronic stress-induced changes in serum inflammatory markers, and in M1 and M2 markers in the PFC.
Fig. 4: Complement component 3 mediates IFNβ–induced neuroinflammation and deficits in social behavior.
Fig. 5: Increased expression of IFI44 and Mx1 in the PFC of depressed subjects.

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Acknowledgements

The authors acknowledge the funding support from US National Institute of Health/National Institute of Mental Health (NIMH) grants (MH120876 and MH121959), and the Merit Review Award (BX004758) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development to AP. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The research funding support from Augusta University is acknowledged. The authors would like to acknowledge Quebec Suicide Brain Bank for human postmortem tissue samples.

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Tripathi, A., Whitehead, C., Surrao, K. et al. Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway. Mol Psychiatry 26, 3043–3059 (2021). https://doi.org/10.1038/s41380-021-01065-6

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