Construction of a nitro-oxidative stress-driven, mechanistic model of mood disorders: A nomothetic network approach

Abstract

Major depression is accompanied by increased IgM-mediated autoimmune responses to oxidative specific epitopes (OSEs) and nitric oxide (NO)-adducts. These responses were not examined in bipolar disorder type 1 (BP1) and BP2. IgM responses to malondialdehyde (MDA), phosphatidinylinositol, oleic acid, azelaic acid, and NO-adducts were determined in 35 healthy controls, and 47 major depressed (MDD), 29 BP1, and 25 BP2 patients. We also measured serum peroxides, IgG to oxidized LDL (oxLDL), and IgM/IgA directed to lipopolysaccharides (LPS). IgM responses to OSEs and NO-adducts (OSENO) were significantly higher in MDD and BP1 as compared with controls, and IgM to OSEs higher in MDD than in BP2. Partial Least Squares (PLS) analysis showed that 57.7% of the variance in the clinical phenome of mood disorders was explained by number of episodes, a latent vector extracted from IgM to OSENO, IgG to oxLDL, and peroxides. There were significant specific indirect effects of IgA/IgM to LPS on the clinical phenome, which were mediated by peroxides, IgM OSENO, and IgG oxLDL. Using PLS we have constructed a data-driven nomothetic network which ensembled causome (increased plasma LPS load), adverse outcome pathways (namely neuro-affective toxicity), and clinical phenome features of mood disorders in a data-driven model. Based on those feature sets, cluster analysis discovered a new diagnostic class characterized by increased plasma LPS load, peroxides, autoimmune responses to OSENO, and increased phenome scores. Using the new nomothetic network approach, we constructed a mechanistically transdiagnostic diagnostic class indicating neuro-affective toxicity in 74.3% of the mood disorder patients.

Introduction

There is now evidence that major depressive disorder (MDD) and bipolar disorder (BD) are accompanied by immune activation and mild chronic inflammation [[1], [2], [3], [4]]. Recently, the early macrophage-T lymphocyte theory of depression [1] was reconceptualized as the IRS-CIRS theory of mood disorders [5]. This theory considers that activation of the immune-inflammatory responses system (IRS) is accompanied by activation of the compensatory immune-regulatory system (CIRS), which regulates the primary IRS [5]. In mood disorders, activation of the IRS is indicated by increased levels of pro-inflammatory cytokines belonging to the M1 macrophage, T helper (Th)-1, Th-2, and Th-17 lineages, while CIRS activation is indicated by increased production of anti-inflammatory products including soluble interleukin (IL)-1 receptor antagonist (sIL-1RA), sIL-2R, and interleukin (IL)-10 [5].

IRS responses are accompanied by activation of neuro-oxidative and neuro-nitrosative pathways whereby reactive oxygen and nitrogen species (RONS) are generated including superoxide, peroxides, nitric oxide (NO), and, consequently, peroxynitrite [6,7]. In physiological conditions, RONS have a role in signaling, and are counterbalanced by antioxidants, either antioxidant enzymes or proteins [6,8]. Lowered antioxidant defenses and/or increased production of RONS may cause increased nitro-oxidative stress toxicity (NOSTOX).

Indicants of RONS/NOSTOX are observed in mood disorders, including increased levels of total peroxides, nitric oxide (NO), and lipid peroxidation in MDD or a major depressive episode (MDE) [3,6,[9], [10], [11], [12]] and BD [[13], [14], [15], [16], [17]]. Recent meta-analyses in both MDD and BD show lowered levels of serum antioxidants and increased RONS and NOSTOX indicating damage to lipids, proteins, DNA, and mitochondria [18,19]. In those disorders, nitro-oxidative toxicity to lipids is driven by lowered levels or activities of key antioxidants including lecithin cholesterol acyltransferase (LCAT), the high-density lipoprotein cholesterol and paraoxonase-1 (PON1) complex, vitamin E, coenzyme Q10, glutathione, and glutathione peroxidase [8,[20], [21], [22], [23], [24], [25], [26]].

Impairments in these lipid–targeting antioxidant defenses and repair mechanisms are accompanied by increased production of RONS and peroxynitrite, which increase risk to lipid peroxidation, oxidative damage to lipid membranes, and the production of reactive aldehydes including malondialdehyde (MDA) and other immunogenic oxidative specific epitopes (OSEs) such as azelaic acid, oxidized phospholipids e.g. phosphatidylinositol (Pi), and oxidized LDL (oxLDL) [6,7,27]. In addition, increased RONS including NO may cause increased nitrosylation, namely the binding of nitroso molecules to proteins, thereby forming nitrosylated proteins, e.g. NO-tryptophan, NO-tyrosine, and NO-cysteinyl [27,28]. Consequently, IgM/IgG autoimmune responses may be generated against these OSEs and nitrosylated proteins, which, in turn, may cause cellular dysfunctions including in signaling and apoptosis [27,28].

Increased IgM responses to conjugated MDA, azelaic acid, Pi, and oleic acid, and increased IgG-mediated autoimmune responses to oxLDL were reported in MDD/MDE [6,27,29,30]. In addition, both BP1 and MDD, but not BP2, are accompanied by increased IgM-mediated autoimmune responses directed against NO-adducts [28]. Nevertheless, there are no data whether BD or BD type 1 (BP1) and BP2 are accompanied by increased IgM responses to OSEs and whether both IgM responses to OSEs and NO-adducts are associated.

Highly significant associations between IgM responses directed against OSEs and NO-adducts, on the one hand, and IgM/IgA responses to LPS of Gram-negative bacteria, on the other, were observed in MDD [30]. Causal reasoning suggests that increased bacterial translocation due to increased gut permeability (leaky gut) may cause IRS and RONS activation and NOSTOX through stimulation of the Toll-Like Receptor (TLR)-2/4 complex and activation of the microbiota-gut-immune-glia (MGIG) axis [[31], [32], [33]]. Nevertheless, there are no data whether the associations between increased LPS load and mood disorders are mediated by increased RONS/NOSTOX. Furthermore, no research has attempted to construct a nomothetic network model [34,35] of mood disorders using causome data (including LPS load), adverse outcome pathways (AOPs, namely increased total peroxides, IgG to oxLDL, IgM to OSENO), and the phenome of mood disorders (including severity of illness and mood disorder phenotypes).

Hence, the current study was conducted to a) examine whether IgM responses to OSENO are increased in BP1/BP2 and MDD as compared with controls, b) examine whether the associations between increased LPS load and the clinical phenome of mood disorders are mediated by increased RONS/NOSTOX, and c) construct a nomothetic network, which ensembles the causome, AOPs, and phenome feature sets of mood disorders.