Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets

Abstract

The involvement of central and peripheral inflammation in the pathogenesis and prognosis of major depressive disorder (MDD) has been demonstrated. The increase of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-18, and TNF-α) in individuals with depression may elicit neuroinflammatory processes and peripheral inflammation, mechanisms that, in turn, can contribute to gut microbiota dysbiosis. Together, neuroinflammation and gut dysbiosis induce alterations in tryptophan metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related mechanisms, and glutamate-mediated excitotoxicity. This review aims to highlight the inflammatory mechanisms (neuroinflammation, peripheral inflammation, and gut dysbiosis) involved in the pathophysiology of MDD and to explore novel anti-inflammatory therapeutic approaches for this psychiatric disturbance. Several lines of evidence have indicated that in addition to antidepressants, physical exercise, probiotics, and nutraceuticals (agmatine, ascorbic acid, and vitamin D) possess anti-inflammatory effects that may contribute to their antidepressant properties. Further studies are necessary to explore the therapeutic benefits of these alternative therapies for MDD.

Keywords: anti-inflammatory approaches; gut dysbiosis; inflammation; major depressive disorder.

Figure 1

Mechanisms underlying microglial and astrocytic activation during neuroinflammation. (A) The neuroinflammatory process is mainly characterized by the activation of glial cells, such as astrocytes and microglia. Activation of these cells involves alterations in gene expression, which induce morphological and functional changes, characterized mainly by the synthesis and release of pro-inflammatory mediators. (B) Microglia activation can occur through pathogen-associated molecular patterns (PAMPs) as well as damage-associated molecular patterns (DAMPs). These factors activate Toll-like receptors (TLR) present on the microglial membrane. Once activated, these receptors activate the adaptor protein myeloid differentiation factor 88 (MyD88), which in turn modulates downstream pathways that promote the activation and translocation of nuclear factor kappa-B (subunits p50/p65) and the transcription factor activator protein-1 (AP-1). Together, these transcription factors induce the expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, pro-IL-1β, inducible nitric oxide synthase (iNOS), as well as components of the NLRP3 inflammasome (ASC, pro-caspase-1, NLRP3). Subsequently, the NLRP3 inflammasome can be activated via reactive oxygen species (ROS), P2X7 purinergic receptors, and TLRs that are activated by DAMPs and PAMPs, respectively. NLRP3 activation promotes caspase activation, which cleave pro-IL-1β and pro-IL-18 into IL-1β and IL-18, respectively. In addition, during microglial activation, mediators such as TNF-α, IL-1α, and complement component 1q (C1q) are synthesized and released. These mediators, in turn, activate astrocytes (reactive astrocytes). (C) Reactive astrocytes lose their ability to maintain glutamate homeostasis. They also tend to facilitate the release of glutamate. Consequently, a substantial increase in glutamate in the extracellular medium induces an intense influx of calcium ions (Ca²⁺) mainly via N-methyl D-aspartate (NMDA) receptors. This ionic influx favors an impairment in the ionic gradient of the mitochondrial membrane and the endoplasmic reticulum. The rupture of these organelles, in turn, induces the release of calcium from these intracellular stores. The resulting increase in intracellular calcium concentration results in the activation of enzymes that degrade proteins, lipids, and DNA. These mechanisms also favor apoptotic neuronal death.

Figure 2

Inflammatory Pathways in MDD. Peripheral inflammation caused by stress, gut inflammation, and lipopolysaccharide (LPS) leakage activates the immune system and leads to increased levels of proinflammatory cytokines. This can cause blood–brain barrier (BBB) disruption, allowing these inflammatory molecules to reach the central nervous system (CNS). In the brain, these molecules contribute to neuroinflammation with the activation of glial cells and further release of proinflammatory cytokines, leading to activation of the hypothalamus-pituitary-adrenal (HPA) axis and cortisol release. This vicious cycle between peripheral inflammation and central neuroinflammation appears to be related to the onset of depressive symptoms and other comorbidities seen in MDD. Thus, molecules capable of controlling these inflammatory processes, such as agmatine, vitamin D, ascorbic acid (vitamin C), and probiotics, as well as non-pharmacological approaches such as physical exercise, are promising therapeutic strategies for the supplementary treatment and management of MDD.