Flavins and Flavoproteins in the Neuroimmune Landscape of Stress Sensitization and Major Depressive Disorder

Major Depressive Disorder (MDD) is a common and severe neuropsychiatric condition resulting in irregular alterations in affect, mood, and cognition. Besides the well-studied neurotransmission-related etiologies of MDD, several biological systems and phenomena, such as the hypothalamic-pituitary-adrenal (HPA) axis, reactive oxygen species (ROS) production, and cytokine signaling, have been implicated as being altered and contributing to depressive symptoms. However, the manner in which these factors interact with each other to induce their effects on MDD development has been less clear, but is beginning to be understood. Flavins are potent biomolecules that regulate many redox activities, including ROS generation and energy production. Studies have found that circulating flavin levels are modulated during stress and MDD. Flavins are also known for their importance in immune responses. This review offers a unique perspective that considers the redox-active cofactors, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), as vital substrates for linking MDD-related maladaptive processes together, by permitting stress-induced enhancement of microglial interleukin-1 beta (IL-1β) signaling.