The role of macrophage polarization on bipolar disorder: Identifying new therapeutic targets.
OBJECTIVE
Bipolar disorder is a chronic, severe and disabling disease; however, its pathophysiology remains poorly understood. Recent evidence has suggested that inflammation and immune dysregulation play a significant role in the pathophysiology of bipolar disorder. This review is aimed to highlight the importance of systemic inflammation in modulating the inflammatory response of microglia and hence its potential involvement with bipolar disorder. We also discuss novel therapeutic strategies that emerge from this new research.


METHODS
This article presents a theoretical synthesis of the effects of systemic inflammation on the immune response of the central nervous system in bipolar disorder. The complex relationship between stress, pro-inflammatory cytokines and microglial dysfunction is summarized, emphasizing the role of the kynurenine pathway in this process and, consequently, their effects on neuronal plasticity.


RESULTS
Bipolar patients demonstrate increased serum levels of pro-inflammatory cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor-α) and lower hypothalamic-pituitary-adrenal axis sensitivity. This imbalance in the immune system promotes a change in blood-brain barrier permeability, leading to an inflammatory signal spread in the central nervous system from the periphery, through macrophages activation (M1 polarization). Chronic microglial activation can result in neuronal apoptosis, neurogenesis inhibition, hippocampal volume reduction, lower neurotransmitters synthesis and cytotoxicity, by increasing glutamate production and kynurenine metabolism.


CONCLUSIONS
This review provides an overview of the mechanisms involved in the immune system imbalance and its potential involvement in the pathophysiology of bipolar disorder. Consequently, new strategies that normalize the immune-inflammatory pathways may provide a valuable therapeutic target for the treatment of these disorders.
Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil Postgraduate Program in Psychiatry and Behavioral Science, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Bruna M
BM
Ascoli
Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil Postgraduate Program in Pharmacology and Therapeutics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Luiza P
LP
Géa
Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil Laboratory of Pharmacology and Physiology, Universidade de Caxias do Sul (UCS), Caxias do Sul, Brazil.
Rafael
R
Colombo
Laboratory of Molecular Biology and Bioinformatics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Florência M
FM
Barbé-Tuana
Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil Postgraduate Program in Psychiatry and Behavioral Science, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
Flávio
F
Kapczinski
Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil Postgraduate Program in Psychiatry and Behavioral Science, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil Postgraduate Program in Pharmacology and Therapeutics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil Department of Pharmacology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil adrianerrosa@gmail.com.
Adriane Ribeiro
AR
Rosa
D000818:Animals; D001714:Bipolar Disorder / Q000276:immunology* / Q000503:physiopathology*; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007249:Inflammation / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D017628:Microglia / Q000276:immunology*; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D051381:Rats
D016207:Cytokines
Bipolar disorder; inflammation; macrophage; microglia; polarization