Neuroinflammation-A Crucial Factor in the Pathophysiology of Depression-A Comprehensive Review

Abstract

Depression is a multifactorial psychiatric condition with complex pathophysiology, increasingly linked to neuroinflammatory processes. The present review explores the role of neuroinflammation in depression, focusing on glial cell activation, cytokine signaling, blood-brain barrier dysfunction, and disruptions in neurotransmitter systems. The article highlights how inflammatory mediators influence brain regions implicated in mood regulation, such as the hippocampus, amygdala, and prefrontal cortex. The review further discusses the involvement of the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, and the kynurenine pathway, providing mechanistic insights into how chronic inflammation may underlie emotional and cognitive symptoms of depression. The bidirectional relationship between inflammation and depressive symptoms is emphasized, along with the role of peripheral immune responses and systemic stress. By integrating molecular, cellular, and neuroendocrine perspectives, this review supports the growing field of immunopsychiatry and lays the foundation for novel diagnostic biomarkers and anti-inflammatory treatment approaches in depression. Further research in this field holds promise for developing more effective and personalized interventions for individuals suffering from depression.

Keywords: astrocytes; cytokines; hypothalamic–pituitary–adrenal axis; major depressive disorder; microglia; neuroinflammation; neurotoxicity; neurotransmitters.

Figure 1

Neuroinflammatory responses in the brain during acute and chronic stress/depression. This model explains how chronic stress contributes to the pathophysiology of depression by promoting a proinflammatory state in the brain, suggesting that targeting inflammation may be beneficial in treating stress-related mental disorders.

Figure 2

The role of the kynurenine pathway in neuroinflammation and depression: impact of proinflammatory cytokines on neurotransmitter balance and cognitive dysfunction. Proinflammatory cytokines and IDO activation: proinflammatory cytokines (IL-6, TNF-α) stimulate IDO activity in peripheral macrophages. IDO catalyzes the conversion of tryptophan to kynurenine, depleting tryptophan, which is essential for serotonin synthesis. This reduction in serotonin is associated with depressive symptoms. Transport and metabolism of kynurenine: kynurenine crosses the blood–brain barrier, where it is metabolized by astrocytes and microglia. In astrocytes, kynurenine is converted to kynurenic acid by kynurenine aminotransferase II (KAT II). Kynurenic acid acts as an antagonist at α7-nicotinic acetylcholine receptors (α7nAChRs), reducing the release of dopamine, serotonin, and glutamate. This leads to cognitive dysfunction. Quinolinic acid and neurotoxicity: In microglia, kynurenine is metabolized by kynurenine 3-monooxygenase (KMO) and 3-hydroxy anthranilic acid oxidase (3-HAO) to quinolinic acid. Quinolinic acid is a potent NMDA receptor agonist, leading to excitotoxicity and lipid peroxidation. These processes contribute to oxidative stress, neurodegeneration, and depressive symptoms.

Figure 3

Interaction between peripheral and central inflammation, brain inflammation, and the HPA axis in depression. (a) Peripheral inflammation: peripheral immune cells, such as monocytes and lymphocytes, release pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) and chemokines in response to inflammation. These cytokines can enter the bloodstream, signaling inflammation throughout the body. (b) ROS: Excessive inflammation leads to the generation of ROS, which are highly reactive molecules that damage cells and amplify inflammatory signaling. (c) Communication to the brain: Cytokines from peripheral inflammation can pass through the BBB or signal through the endothelial cells of the BBB, triggering inflammation in the brain. This process activates microglia and astrocytes (key immune and support cells in the brain), which then release their proinflammatory cytokines, such as IL-1, IL-6, and TNF-α. (d) Brain inflammation: chronic brain inflammation contributes to neurological disorders, cognitive deficits, and behavioral changes such as anxiety or depression. The inflamed brain, as shown in the figure, is represented by activated microglia and astrocytes. (e) Impact on the HPA axis: Inflammation influences the HPA axis: Stress or inflammatory signals stimulate the hypothalamus to release CRH again. CRH triggers the pituitary gland to secrete ACTH. ACTH acts on the adrenal glands, causing the release of the stress hormone cortisol. Cortisol usually has anti-inflammatory effects, but prolonged activation (chronic stress) can dysregulate this system, leading to persistent inflammation and impaired stress responses. (f) Psychological effects: Stress and inflammation are described as affecting mental health and can cause depressive symptoms and brain dysfunction.

Figure 4

Novel inflammatory biomarkers for depression.

Figure 5

The complex relationship between cortisol and inflammation.