The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis

Abstract

Schizophrenia and especially defcit schizophrenia (DSCZ)) are characterized by highly significantly increased activities of neuroimmunotoxic pathways and a generalized cognitive decline (G-CoDe). There are no data whether the interleukin(IL)-6/IL-23/Thelper-17 (IL6/IL23/Th17)-axis is more associated with DSCZ than with non-deficit schizophrenia (NDSCZ) and whether changes in this axis are associated with the G-CoDe and the phenome (a factor extracted from all symptom domains) of schizophrenia. This study included 45 DSCZ and 45 NDSCZ patients and 40 controls and delineated whether the IL6/IL23/Th17 axis, trace elements (copper, zinc) and ions (magnesium, calcium) are associated with DSCZ, the G-CoDe and phenome of schizophrenia. Increased plasma IL-23 and IL-6 levels were associated with Th17 upregulation, assessed as a latent vector (LV) extracted from IL-17, IL-21, IL-22, and TNF-α. The IL6/IL23/Th17-axis score, as assessed by a LV extracted from IL-23, IL-6, and the Th17 LV, was significantly higher in DSCZ than in NDSCZ and controls. We discovered that 70.7% of the variance in the phenome was explained by the IL6/IL23/Th17-axis (positively) and the G-CoDe and IL-10 (both inversely); and that 54.6% of the variance in the G-CoDe was explained by the IL6/IL23/Th17 scores (inversely) and magnesium, copper, calcium, and zinc (all positively). In conclusion, the pathogenic IL6/IL23/Th17-axis contributes to the generalized neurocognitive deficit and the phenome of schizophrenia and especially that of DSCZ due to its key role in peripheral inflammation and neuroinflammation and its consequent immunotoxic effects on neuronal circuits. These clinical impairments are more prominent in subjects with lowered IL-10, magnesium, calcium, and zinc.

In schizophrenia, the effects of the IL-6/IL-23/Th17 axis on health-related quality of life and disabilities are partly mediated by generalized cognitive decline and the symptomatome

“…As previously stated, these cytokines all show neuroimmunotoxic properties and, more crucially, are associated with the cognitive deficits and symptomatome of schizophrenia (Al-Hakeim et al, 2022). In addition, one validated latent vector could be extracted from these cytokines, validating the novel concept of the “neuroimmunotoxic IL6IL23Th17 axis” (Al-Hakeim et al, 2022).…”

“…Although a common latent trait underpins IL-6, IL-23, and the Th17-linked cytokines (IL-17, IL-21, IL-22, and TNF-α), we also found that both IL-6 and IL-23 are significantly linked to the Th-17-associated cytokines and, as a result, to the G-CoDe, symptomatome, and, consequently, to HR-QoL and disabilities. As previously discussed, IL-23 and IL-6 are important inducers of proliferation and survival of the pathogenic Th-17 phenotype as well as IL-17 production (Al-Hakeim et al, 2022). Increased IL-6, IL-23, and Th-17-related cytokines have a variety of neuroimmunotoxic effects, including activating autoimmune responses, maintaining persistent peripheral inflammation and neuroinflammation, lowering hippocampal neurogenesis, microglial activation, CNS tissue damage, and induction of the JAK-STAT and MAP-kinase pathways (Nitsch et al, 2019; Tahmasebinia and Pourgholaminejad, 2017; Liu et al, 2014; Langrish et al, 2005; Leavy et al, 2014; Lee et al, 2022; Liang et al, 2010).…”

“…We recently created a novel neuroimmunotoxic pathway index in schizophrenia, particularly deficit schizophrenia, by connecting IL-6, IL-23, and IL-17 to critical actors such as IL-21, IL-22, and TNF-α (Al-Hakeim et al, 2022). As previously stated, these cytokines all show neuroimmunotoxic properties and, more crucially, are associated with the cognitive deficits and symptomatome of schizophrenia (Al-Hakeim et al, 2022). In addition, one validated latent vector could be extracted from these cytokines, validating the novel concept of the “neuroimmunotoxic IL6IL23Th17 axis” (Al-Hakeim et al, 2022).…”

Increased AGE-RAGE axis stress in methamphetamine (MA) abuse and MA-induced psychosis: associations with oxidative stress and increased atherogenicity

“…MA use may cause cardiovascular disease including atherosclerotic plaque formation (32). Moreover, MA abuse may cause changes in calcium, magesium and copper metabolism (33)(34)(35), which are associated with schizophrenia (36,37) and increased atherogenicity (11,38). However, no previous papers examined AGE, sRAGE, calcium, magnesium, and copper levels in MA dependence and MIP, and their association with OSTOX, ANTIOX, and atherogenicity markers.…”