Functional immune responses to PI3K pathway inhibition in PBMCs from schizophrenia patients without metabolic syndrome.

INTRODUCTION

Schizophrenia (SCZ) is a mental disorder characterized by complex interaction between genetic and environmental factors, mediated by molecular events, including alterations in components of the PI3K/GSK3/mTOR signaling pathway. However, considering that metabolic dysregulation is known to strongly influence this inflammatory signaling, it remains unclear whether peripheral immune cells from patients with SCZ without metabolic syndrome (MetS) exhibit altered cytokine responses following pharmacological modulation of this pathway.

METHODS

Addressing this gap, peripheral blood from 11 patients with SCZ and 11 healthy controls matched 1:1 by sex, age, and educational level were collected to obtain plasma and Peripheral Blood Mononuclear Cells (PBMCs). PBMCs were incubated with PI3K, GSK3 and mTORC1 inhibitors for 30 min and stimulated or not with phytohaemagglutinin (PHA) for 24 h. Plasma and cells supernatant of IL-6, IL-1β, IL-17 A, TNF, MCP-1 and IL-10 were quantified by ELISA and CBA.

RESULTS

Plasma cytokines levels did not differ between groups. However, in basal conditions, cells from SCZ patients produced lower levels of IL-10 compared to controls. Non-selective PI3K inhibitor suppressed TNF and MCP-1 and increased IL-1β in both groups, with dose-dependent effects. PI3K inhibitors selectively reduced IL-10 in non-stimulated cells from controls. GSK3 inhibitor had no significant effects on cytokine production, and inhibition of mTORC1 suppressed MCP-1 in both groups. None of the inhibitors treatments significantly altered IL-6 or IL-17 A levels under any condition.

CONCLUSION

Collectively, these findings provide preliminary functional observations regarding cytokine responses following pharmacological modulation of PI3K/mTOR-related signaling in peripheral immune cells of patients with SCZ without MetS.