Attenuated inflammatory response of monocyte-derived macrophage from patients with BD: a preliminary report

Adriane R Rosa,Rafael Colombo,Fátima Theresinha Costa Rodrigues Guma,Bruna M Ascoli,Bárbara Antqueviezc,Elisa Brietzke,Mariana M Parisi,Luiza P Géa,Giovana Bristot,Florencia M Barbé-Tuana,Flávio Kapczinski

doi:10.1186/s40345-019-0148-x

Abstract

BackgroundInnate immune system dysfunction has been recognized as an important element in the pathophysiology of bipolar disorder (BD). We aimed to investigate whether there are differences in the response of macrophages derived from patients in the early stages and late stages of BD and healthy subjects.MethodsHuman monocytes purified from peripheral blood mononuclear cells (PBMCs) of patients with BD type I (n = 18)—further classified into early- and late stage BD patients according to their functioning- and from healthy individuals (n = 10) were differentiated into macrophages in vitro. Monocyte-derived macrophages (M) were exposed to IFNγ plus LPS-M(IFNγ + LPS)- or IL-4-M(IL-4)—to induce their polarization into the classical (also called M1) or alternative (also called M2) activation phenotypes, respectively; or either Mψ were not exposed to any stimuli characterizing the resting state (denominated M0). In vitro secretion of cytokines, such as IL-1β, IL-6, IL-10, and TNF-α, was used as an index of macrophage activity.ResultsM(IFNγ + LPS) from late-stage BD patients produced less amount of IL-1β, IL-6, and IL-10 when compared to early-stage BD patients and healthy controls. Following alternative activation, M(IL-4) derived from late-stage patients secreted less IL-6 compared to the other groups. TNFα was less secreted by all macrophage phenotypes derived from late-stage patients when compared to healthy controls only (p < 0.005). Mψ from late-stage patients exhibited lower production of IL-1β and IL-10 compared to macrophages from healthy subjects and early-stage patients respectively. Interestingly, cytokines secretion from M(IFNγ + LPS), M(IL-4) and Mψ were similar between early-stage patients and healthy controls.ConclusionOur results suggest a progressive dysfunction in the response of peripheral innate immune cells of BD patients in the late stages of the illness. This failure in the regulation of the immune system function may be implicated in the multisystemic progression of BD.

Highlights

A remarkable recent shift in the understanding of bipolar disorder (BD) pathophysiology was the systematic documentation of its clinical and neurobiological progression (Berk et al 2017; Kapczinski et al 2014)
Early-stage BD patients were defined as exhibiting a mean Functioning Assessment Short Test (FAST) score lower than 11, while late-stage patients were those with a mean FAST score higher than 40 (Bonnín et al 2018)
As expected from the selection criteria, subjects with BD-L had a higher mean FAST score when compared to early-stage patients and healthy volunteers F = 50.874; p < 0.001)

Summary

Introduction

A remarkable recent shift in the understanding of bipolar disorder (BD) pathophysiology was the systematic documentation of its clinical and neurobiological progression (Berk et al 2017; Kapczinski et al 2014). The validity of different methods that enable to discriminate in which point of the clinical and neurobiological progression of BD each patient would it remain under debate (Kapczinski et al 2009). The Functioning Assessment Short Test (FAST) as previously described by Rosa et al (2014), was used to discriminate between patients at early and late stages of BD. We aimed to investigate whether there are differences in the response of macrophages derived from patients in the early stages and late stages of BD and healthy subjects

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