Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression

Maria S. Simon*, Carmen Schiweck, Gara Arteaga-Henríquez, Sara Poletti, Bartholomeus C.M. Haarman, Wim A. Dik, Markus Schwarz, Elske Vrieze, Olya Mikova, Silke Joergens, Richard Musil, Stephan Claes, Bernhard T. Baune, Marion Leboyer, Francesco Benedetti, Roberto Furlan, Raf Berghmans, Harm de Wit, Annemarie Wijkhuijs, Volker AroltNorbert Müller, Hemmo A. Drexhage

*Corresponding author for this work

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Abstract

Background: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD). Methods: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters. Results: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation. Conclusions: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF “inflammaging”, as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging.

Original languageEnglish
Article number110391
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume111
DOIs
Publication statusPublished - 20 Dec 2021

Bibliographical note

Funding Information:
MSS was employed in the past for some time during data evaluation using the above mentioned third party grant. RM declares personal fees from Otsuka/Lundbeck. SC declares grants from Johnson&Johnson. GAH was supported by the foundation “Immunität und Seele” and by the European Union Horizon 2020 research and innovation programme (N0728018). AW was funded by EU-FP7-PEOPLE-2009-IAPP “PSYCH-AID”. VA has received compensations for his contributions as member of advisory boards and for presentations for the following companies: AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Otsuka, Sanofi, Servier, and Trommsdorff. He received grants from the German Ministry of Science and Education, the Münster Interdisciplinary Center of Clinical Research, and from the European Union. NM has given presentations for Janssen-Cilag during the last 6 months and was supported by the foundation “Immunität und Seele”. HAD is the coordinator of the project funded by the EU as indicated in the funding section. He has received further grants from the Netherlands Organization for Health Research and Development, the Stanley Medical Research Institute, the Dutch Diabetic Foundation and the JDRF; he has received speaker's fees from AstraZeneca and he serves/ has served on advisory boards of the Netherlands Organization for Health Research and Development, the European Union and the JDRF. The supporters had no role in the study design, data collection, analysis and interpretation, writing of the report, and decision to publish. CS, SP, BCMH, WAD, MS, EV, OM, SJ, BTB, ML, FB, RF, RB, HW, and AW declare no potential conflict of interest.

Funding Information:
This work was supported by the European Commission : EU 7th Framework program (grant number EU-FP7-CP-IP-2008-222963 ) and Horizon 2020 (grant number H2020-SC1-2016-2017/H2020-SC1-2017-Two-Stage-RTD ) grants were received by HAD, Erasmus Medical Center Rotterdam. The funder had no role in the study design, data collection, analysis, and interpretation, writing of the report, and decision to publish.

Publisher Copyright:
© 2021

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