M1/M2 polarization in major depressive disorder: Disentangling state from trait effects in an individualized...

Accumulating evidence indicates the specific involvement of inflammatory processes in major depressive disorder (MDD), particularly affecting innate immunity. Most immune alterations have so far been determined based on plasma or cerebrospinal fluid cytokine levels. To precisely characterize putative innate immune-mediated mechanisms in MDD pathogenesis, we sought to disentangle "state" from "trait" effects in a patient-specific cell model by quantifying the impact of patient-derived autologous sera (AS) on patient-specific monocyte-derived macrophages (Mo-MФs) polarization in vitro. Mo-MФs were generated from 28 patients with moderate to severe MDD and 28 age-, sex-, smoking status- and BMI-matched healthy controls (HC). Cells were treated either with AS or fetal calf serum (FCS) and polarized into M1 (LPS), M2 (IL-10, IL-4, TGF-β) or M0 (unstimulated) macrophages. Polarization capacity was quantified by means of specific M1 (CCR7, CD86, CXCL10, IL-12p70, TNF-α, IL-6, IL-1β, IL-12p40, IL-23, IP-10) and M2 (CD206, IL-10, TARC, IL-1RA) markers. Compared to HC, significantly increased M1-polarization was observed for MDD patients in the presence of FCS, however, polarization in AS enriched media determined an increased M2-polarization in patients. Moreover, female MDD patients exhibited increased M1- and decreased M2-polarization in both conditions compared to male MDD patients. Our data suggests that Mo-MФs derived from patients with MDD exhibit facilitated M1-polarization under traditional cell culture conditions and an increased potential for M2-polarization when cultured in AS. Striking inter-individual variation and pronounced gender effects highlight the potential utility of our personalized cell model-based approach to aid diagnostic and therapeutic decisions.