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Background: Schizophrenia (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. Methods: We 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. Results: We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA) as well as 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 species and the expression of inflammasome system elements in SMI. Conclusions: Based on these results, we suggest a link between systemic inflammasome activation/dysregulation and cholesterol load in SMI. Our findings further the understanding of possible underlying inflammatory and metabolic mechanisms and may expose important therapeutic targets in SMI.

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