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

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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
Number of pages11
JournalProgress in Neuro-Psychopharmacology & Biological Psychiatry
Early online date23-Jun-2021
Publication statusE-pub ahead of print - 23-Jun-2021


  • Major depressive disorder
  • Childhood adversity
  • Inflammation
  • Cholesterol pathway
  • Apoptosis
  • PCR

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