TY - JOUR
T1 - Higher immune-related gene expression in major depression is independent of CRP levels
T2 - results from the BIODEP study
AU - Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium
AU - Sforzini, Luca
AU - Cattaneo, Annamaria
AU - Ferrari, Clarissa
AU - Turner, Lorinda
AU - Mariani, Nicole
AU - Enache, Daniela
AU - Hastings, Caitlin
AU - Lombardo, Giulia
AU - Nettis, Maria A.
AU - Nikkheslat, Naghmeh
AU - Worrell, Courtney
AU - Zajkowska, Zuzanna
AU - Kose, Melisa
AU - Cattane, Nadia
AU - Lopizzo, Nicola
AU - Mazzelli, Monica
AU - Pointon, Linda
AU - Cowen, Philip J.
AU - Cavanagh, Jonathan
AU - Harrison, Neil A.
AU - Jones, Declan
AU - Drevets, Wayne C.
AU - Mondelli, Valeria
AU - Bullmore, Edward T.
AU - Mondelli, Valeria
AU - Pariante, Carmine M.
AU - Pariante, Carmine M.
N1 - Funding Information:
The authors declare that they have no known conflict of interest that could have appeared to influence the work reported in this paper. Prof. Pariante have received research funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2, as part of the EU-PEARL project. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. Prof. Pariante is also funded by a Senior Investigator award from the National Institute for Health Research (NIHR); the Medical Research Council (grants MR/L014815/1, MR/J002739/1 and MR/N029488/1); the European Commission (EARLYCAUSE grant SC1-BHC-01-2019); the NARSAD; the Psychiatry Research Trust; and the Wellcome Trust (SHAPER, Scaling-up Health-Arts Programme to scale up arts interventions, grant 219425/Z/19/Z). Less than 10% of his support in the last 10 years derives from commercial collaborations, including consultation and speakers fees from Boehringer Ingelheim, Eli Lilly, Compass, Eleusis, GH Research, Lundbeck, and Värde Partners. Dr Mondelli is also funded by MQ: Transforming Mental Health (Grant: MQBF/1 and MQBF/4) and the Medical Research Foundation (Grant: MRF-160-0005-ELP-MONDE).
Funding Information:
We would like to acknowledge the valuable contribution of our colleague Peter de Boer, who sadly passed away in 2020. This research was funded by the Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium [104025/Z/14/Z], which is also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer. This work was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at the South London and Maudsley NHS Foundation Trust and King’s College London, London, the NIHR Cambridge Biomedical Research Centre (Mental Health) and the Cambridge NIHR BRC Cell Phenotyping Hub. All raw data not included in this article can be accessed by request to the NIMA Consortium (please, contact the authors). Dr. Sforzini is supported by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2, as part of the EU-PEARL project; this Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. We would like to gratefully thank all study participants, research teams and laboratory staff, without whom this research would not have been possible. We thank and acknowledge all members of the NIMA Consortium at the time of data collection (see Supplementary Material).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85160927488&partnerID=8YFLogxK
U2 - 10.1038/s41398-023-02438-x
DO - 10.1038/s41398-023-02438-x
M3 - Article
C2 - 37264010
AN - SCOPUS:85160927488
SN - 2158-3188
VL - 13
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 185
ER -
