Higher immune-related gene expression in major depression is independent of CRP levels: results from the BIODEP study

Sforzini, Luca, Cattaneo, Annamaria, Ferrari, Clarissa, Turner, Lorinda, Mariani, Nicole, Enache, Daniela, Hastings, Caitlin, Lombardo, Giulia, Nettis, Maria, Nikkheslat, Naghmeh, Worrell, Courtney, Zajkowska, Zuzanna, Kose, Melisa, Cattane, Nadia, Lopizzo, Nicola, Mazzelli, Monica, Pointon, Linda, Cowen, Philip, Cavanagh, Jonathan, Harrison, Neil ORCID: https://orcid.org/0000-0002-9584-3769, Jones, Declan, Drevets, Wayne, Mondelli, Valeria and Bullmore, Edward 2023. Higher immune-related gene expression in major depression is independent of CRP levels: results from the BIODEP study. Translational Psychiatry 10.1038/s41398-023-02438-x

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Abstract

Compelling evidence demonstrates that some individuals suffering from major depressive disorder (MDD) exhibit increased levels of inflammation. Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone. Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD. We examined 168 individuals from the non-interventional, case–control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (n = 59 with CRP <1, n = 33 with CRP 1–3 and n = 36 with CRP >3 mg/L). We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP. In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP >3 vs. CRP <1 and/or controls), reflecting the gradient of CRP values. Secondary analyses on MDD individuals and controls with CRP values <1 mg/L (usually interpreted as 'no inflammation') confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls. These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels. Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Psychology Cardiff University Brain Research Imaging Centre (CUBRIC)
Additional Information:	AAM can not be stored due to publisher policy. Published version can be added. Once available, please add published version.
Date of First Compliant Deposit:	24 April 2023
Date of Acceptance:	19 April 2023
Last Modified:	03 Jun 2023 05:53
URI:	https://orca.cardiff.ac.uk/id/eprint/158996

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