Abstract
BackgroundSchizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. MethodsWe tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. ResultsWe report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. ConclusionsBased on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.
Highlights
Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with high heritability that adversely impact the individual with large costs to society (Owen et al, 2016; Correll et al, 2015)
In this large population of patients with severe mental illnesses (SMI) and healthy controls we found i) higher plasma levels of IL-18, IL-18BPA, and IL-18R1 in SMI, ii) which was independent of C-reactive protein (CRP) levels in BD, but not in SCZ; iii) elevated mRNA levels of inflammasome genes (NLRP3 and NLRC4), but not IL-18 family members in immune cells isolated from whole blood from pa tients with SMI relative to controls
Iv) we observed correlations between blood lipids and inflammasome system elements in psychotic disorder patients, but not in controls. These results support potential inflammasome activation in severe mental disorders, with different patterns across the psychosis continuum which may be linked to dyslipidemia-related processes in BD and SCZs
Summary
Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with high heritability that adversely impact the individual with large costs to society (Owen et al, 2016; Correll et al, 2015) These psychotic disorders are suggested to be part of a psychosis continuum (Tesli et al, 2014; Moller, 2003; Craddock, 2005), and dysregulated immune responses, inflammation and autoimmunity have been impli cated in their pathophysiology (Khandaker et al, 2015; Pollak et al, 2020). Recent evidence links psychosis to sterile inflammation of the brain or to systemic inflammatory processes that affect the central nervous system (Chen and Nunez, 2010; SayuriYamagata et al, 2017; Rubartelli, 2014) This is supported by dysregulated systemic markers of inflammation and immune activation, with correlations to clinical indices of disease severity (Mørch et al, 2016; Mørch et al, 2017; Wedervang-Resell et al, 2020). Not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients.
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