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

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

PAVING THE ROAD FOR PRECISION MEDICINE: THE ROLE OF STRESS MONITORING AND INFLAMMATION IN DEPRESSION

Major Depressive Disorder (MDD), in many patients, takes the form of a chronic, relapsing-remitting disorder. During past decades, it has become clear that biological changes may underlie MDD (1) . These changes do not only suggest a biological base of mood disorders, but may also be used as tool to predict response and relapse and can hence provide valuable information as to the selection of adequate treatment for patients with MDD. One of the established biological changes in MDD may arise from a disturbed immune system. The interaction between the immune system, and other established changes such as HPA axis alterations, and eventually mood, this pathway is a good candidate for a possible biomarker in MDD (2). During the Mood inflame project, a European cooperation aiming to identify biomarkers of mood disorders, data about the immune cell profile in patients with MDD have been collected. Part one of this doctoral plan is to analyse this data in MDD patients of the Mood inflame project with focus on specific clinical factors that have been linked to inflammation, such as suicide risk and childhood adversity. In a second project, we will explore whether the established differences of autonomic nervous system markers such as heart rate (HR) and its variability (HRV) can be used for state monitoring in depression. Given the important role of stress on depression pathogenesis and HR/HRV we will first adress important questions as to alterations during different states of stress. This includes conducting a systematic review on HR/HRV during stress in depressed patients, and an experimental study, where for the first time, we will re-expose patients with depression to exactly the same stress task, to test their capacity of adaptation to stress, and possibly explain the blunting of HR/HRV. Lastly, we will conduct a clinical trial using ketamine to assess whether rapid changes in mood can be linked to autonomic and/or immune changes. The non-competitive N-methyl-aspartate (NMDA) receptor antagonist ketamine has shown potential for treating MDD by its rapid onset of antidepressant effects (3). Several recently completed clinical trials show good efficacy in reduction of depressive symptoms (4,5) and suicidal ideation (6), albeit only short lasting. We here use ketamine as paradigm to assess the correlation between mood and HRV/immune parameters.status: publishe

Regulation of CD4+ and CD8+ T Cell Biology by Short-Chain Fatty Acids and Its Relevance for Autoimmune Pathology

The gut microbiota encodes a broad range of enzymes capable of synthetizing various metabolites, some of which are still uncharacterized. One well-known class of microbiota-derived metabolites are the short-chain fatty acids (SCFAs) such as acetate, propionate, butyrate and valerate. SCFAs have long been considered a mere waste product of bacterial metabolism. Novel results have challenged this long-held dogma, revealing a central role for microbe-derived SCFAs in gut microbiota-host interaction. SCFAs are bacterial signaling molecules that act directly on host T lymphocytes by reprogramming their metabolic activity and epigenetic status. They have an essential biological role in promoting differentiation of (intestinal) regulatory T cells and in production of the anti-inflammatory cytokine interleukin-10 (IL-10). These small molecules can also reach the circulation and modulate immune cell function in remote tissues. In experimental models of autoimmune and inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis or diabetes, a strong therapeutic potential of SCFAs through the modulation of effector T cell function was observed. In this review, we discuss current research activities toward understanding a relevance of microbial SCFA for treating autoimmune and inflammatory pathologies from in vitro to human studies

Targeting IL-17A signaling in suicidality, promise or the long arm of coincidence? Evidence in psychiatric populations revisited

Interleukin 17 (IL-17) is a potent pro-inflammatory cytokine which plays a role in autoimmune disorders, such as psoriasis and multiple sclerosis, and is important for the defense against pathogens, particularly in the gut. However, IL-17 has recently also gained attention in association with suicidal behavior. In this review, we review the literature regarding IL-17 in psychiatric disorders and suicidality. We also take a closer look at the suicides which occurred in the clinical trial for psoriasis with brodalumab, a monoclonal antibody targeting the IL-17 receptor. Lastly, we discuss potential working mechanisms relevant to neuroinflammation and the possible involvement of IL-17

Heart rate and high frequency heart rate variability during stress as biomarker for clinical depression. A systematic review

The interaction of physical and mental vulnerability and environmental constraints is thought to foster the development of psychiatric disorders such as major depressive disorder (MDD). A central factor in the development of psychopathology is mental stress. Despite some evidence for parasympathetic withdrawal and sympathetic overactivity in MDD, the psychophysiological response to stress in depression is not clear-cut. Given the growing interest in heart rate and heart rate variability as indicators for remote monitoring of patients, it is important to understand how patients with MDD react to stress in a laboratory-controlled environment. We conducted a systematic review of studies using electrocardiography to derive heart rate and heart rate variability during stress in patients with clinical depression. We focused on well-validated stress tasks- the mental arithmetic stress task, the Trier social stress task and public speaking task- to minimize confounding effects due to the nature of the stressor. The majority of studies found hypo-reactivity during stress as a hallmark of depression as evidenced by lower fluctuation in heart rate and heart rate variability in the high-frequency band. We address the potential underlying biological mechanisms, the influence of covariates on these measures and briefly discuss the specificity and potential for remote monitoring by using these variables.status: publishe