Neuroinflammation and Depression: How the Brain's Immune System Affects Mood and Memory

What is neuroinflammation?

Inflammation is a normal protective response of the immune system. In the brain, microglia serve as the resident immune cells: at rest, they monitor the state of neurons and clear damaged synapses. During infection or stress, microglia activate and release pro-inflammatory cytokines — signaling molecules: interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β).

Under normal conditions, the brain's inflammatory response is brief and ends with recovery. Under chronic stress, a sedentary lifestyle, or a pro-inflammatory diet, microglia remain in an activated state for extended periods. This condition is called neuroinflammation, and its consequences are measurable.

What is the link between cytokines and depression?

In 2025, Gedek and colleagues (International Journal of Molecular Sciences) published a systematic review and meta-analysis of 17 studies involving 1,371 patients with major depressive disorder and 861 healthy controls. The analysis focused exclusively on patients with a first depressive episode — those who had not yet received antidepressants — ruling out any treatment effect on cytokine levels.

Results in first-episode patients:

• IL-6: standardized mean difference (SMD) = 1.40 (95% CI: 0.53–2.27), p = 0.002
• TNF-α: SMD = 1.30 (95% CI: 0.41–2.18), p = 0.004
• IL-2: SMD = 1.81 (95% CI: 0.45–3.17), p = 0.009

Among patients who had never taken medication, the pattern was similar: IL-6 SMD=1.08, TNF-α SMD=0.73. This confirms that elevated cytokines are a biological feature of depression, not an artifact of treatment. The direction of causality (inflammation causing depression, or the reverse) cannot be determined by this meta-analysis alone, though the cumulative evidence points to a bidirectional relationship.

What happens to synapses during neuroinflammation?

Kokkosis and colleagues (Glia, 2023) studied mice subjected to chronic social stress. Approximately 80% of the animals displayed depression-like behavior — reduced interest in a sucrose solution and social avoidance. In the medial prefrontal cortex of these mice:

• microglial density increased by 26%;
• microglial proliferation capacity rose 3-fold;
• the rate of synaptic element phagocytosis increased 4-fold;
• infiltration of peripheral immune cells into the brain doubled.

Synapse phagocytosis is a normal pruning process for neural connections. Under chronic stress it accelerates pathologically: the brain loses functional connections faster than it can restore them. This is the structural substrate for reduced cognitive function and mood disturbances.

Shen and colleagues (Advanced Science, 2025) identified a specific molecular pathway: activated microglia release IL-6, which triggers apoptosis of astrocytes in the hippocampus — the brain structure critical for memory — via IL-6 receptors. Blocking the P2X7R receptor on microglia reduced IL-6 release and protected astrocytes.

How is neuroinflammation linked to the risk of dementia?

Leonardo and Fregni (Frontiers in Aging Neuroscience, 2023) conducted a meta-analysis of 79 studies (46 cross-sectional and 33 prospective) on inflammation and cognitive function in older adults. In the 33 longitudinal studies with a mean follow-up of approximately 58 months:

• Elevated IL-6 (above 3.1 pg/mL) predicted cognitive decline: odds ratio OR = 1.34 (95% CI: 1.13–1.56).
• In patients with Alzheimer's disease compared to healthy controls: IL-6 Hedges' g = 0.46, sTNFR-1 g = 0.74.
• CRP and TNF-α did not reach statistical significance in longitudinal models — IL-6 proved to be the most consistent long-term predictor.

These data are observational: the association is established, but there are insufficient controlled trials demonstrating that reducing IL-6 prevents dementia.

What reduces neuroinflammation: intervention data?

Zheng and colleagues (Brain, Behavior, & Immunity — Health, 2026) conducted a dose-response meta-analysis of 29 RCTs with 2,253 participants examining tai chi, qigong, yoga, and mindfulness programs (MBSR). The optimal dose was 600–1,000 MET-min/week (approximately 150–250 min/week of moderate intensity). At this dose:

• IL-6: SMD = −0.47 (significant reduction);
• IL-1β: SMD = −0.90 (significant reduction);
• IL-10 (anti-inflammatory cytokine): SMD = +0.87 (significant increase);
• BDNF (neurotrophic factor): SMD = +1.08 (significant increase).

Keshani and colleagues (Nutrition Reviews, 2025) analyzed 33 RCTs (3,476 participants) examining the Mediterranean diet. It significantly reduced hs-CRP and IL-6 — particularly in participants under 60 and in studies lasting up to 12 weeks.

Exercise without a meditative component (standard aerobic or resistance training) also affects inflammation in depression, but the data are more heterogeneous. Song and colleagues (Life, 2025; 13 RCTs, 1,004 participants) showed that physical exercise significantly reduces depressive symptoms (SMD = −0.59), but the combined effect on CRP, IL-6, and TNF-α did not reach significance. The exception was interventions of 8–12 weeks, where TNF-α was significantly reduced: MD = −0.73.