Inflammatory signaling mechanisms in bipolar disorder

Abstract

Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with a high individual and societal burden. While not all patients display overt markers of elevated inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease, and likely explains the elevated rates of comorbid inflammatory illnesses seen in this population. While individual systems have been intensely studied and targeted, a relative paucity of attention has been given to the interconnecting role of inflammatory signals therein. This review presents an updated overview of some of the most prominent pathophysiologic mechanisms in bipolar disorder, from mitochondrial, endoplasmic reticular, and calcium homeostasis, to purinergic, kynurenic, and hormonal/neurotransmitter signaling, showing inflammation to act as a powerful nexus between these systems. Several areas with a high degree of mechanistic convergence within this paradigm are highlighted to present promising future targets for therapeutic development and screening.

Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress–Induced Damage in Patients with Bipolar Disorder

“…Proinflammatory cytokines include interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), whereas anti-inflammatory cytokines include IL-10 and IL-4, which can prevent immune system activation [179][180][181]. Notably, high proinflammatory cytokine levels have been consistently observed in patients with BD, especially during acute episodes [177,180,[182][183][184]. Moreover, patients with BD exhibit reduced anti-inflammatory cytokine levels during the manic phase [185][186][187][188].…”

Blood-brain barrier dysfunction in bipolar disorder: Molecular mechanisms and clinical implications

“…Of note, TNF-α has been hypothesized to contribute to chronic neurodegeneration seen in patients with BD through activation of a positive feedback loop. Specifically, by increasing BBB permeability, peripheral cytokine-recruiting monocytes enter the CNS and can cause up-regulation of NLRP3 inflammasome activity and modulation of glycogen synthase kinase-3β (GSK-3β) activity, which is known to regulate inflammation, mitochondrial metabolism, DNA repair, and apoptosis ( Jones et al., 2021 ). The role of TNF-α in mediation of BBB function is further supported by in vitro models of BMECs derived from pluripotent stem cells of patients with and schizophrenia, which demonstrate decreased BBB integrity and increased permeability compared to controls.…”

Cronobiologia do transtorno afetivo bipolar: uma revisão narrativa

“…Outrossim, sabe-se que indivíduos com TAB apresentam níveis elevados de ativação de células T e diminuição de células T reguladoras, ocorrendo em ambos os episódios -maníaco e depressivo -e que isso normaliza com o tratamento medicamentoso [46]. Soma-se a isso ao fato de que, epidemiologicamente, o TAB associa-se a comorbidades que incluem condições autoimunes, reações de hipersensibilidade (asma, rinite e alergias) e doenças cardiometabólicas, reforçando ainda mais a hipótese imunológica deste distúrbio psiquiátrico [47].…”