Serum inflammatory cytokines in the progression of depression.

Depression involves immune dysregulation, and serum inflammatory cytokines such as IL-1β, IL-6, TNF-α, IFN-γ, and C-reactive protein link peripheral inflammation to brain dysfunction. These cytokines activate innate immune pathways like TLR4, NF-κB, MAPK, and NLRP3 inflammasome, alter tryptophan-kynurenine metabolism via IDO1 and TDO2, impair monoamine neurotransmission, enhance glutamatergic excitotoxicity, reduce BDNF-dependent neuroplasticity, and promote microglia-mediated neuroinflammation. Clinical studies associate cytokine profiles with symptom severity, cognitive dysfunction, suicidality, and illness chronicity. Anti-inflammatory compounds, antidepressants with immunomodulatory effects, and ketamine may work partly by normalizing these cytokine pathways.

Study at a glance

Abstract

Depression is increasingly recognized as a multifactorial disorder in which immune dysregulation contributes substantially to disease initiation, progression, and treatment response. Among the immune mediators implicated, serum inflammatory cytokines-including IL-1β, IL-6, TNF-α, IFN-γ, and C-reactive protein-have emerged as key links between peripheral inflammation and central nervous system dysfunction. These cytokines influence depression-related pathophysiology by activating innate immune signaling pathways, including TLR4, NF-κB, MAPK, and the NLRP3 inflammasome, while also reshaping tryptophan-kynurenine metabolism through IDO1 and TDO2. The resulting alterations impair monoaminergic neurotransmission, enhance glutamatergic excitotoxicity, suppress BDNF-dependent neuroplasticity, and promote microglia-mediated neuroinflammation. Clinical studies further associate inflammatory cytokine profiles with symptom severity, cognitive dysfunction, suicidality, and illness chronicity, supporting their potential value as biologically informative markers in depression. Emerging therapeutic evidence indicates that anti-inflammatory bioactive compounds, conventional antidepressants with immunomodulatory properties, and rapid-acting agents such as ketamine may partially exert their effects by normalizing cytokine-associated pathways. This review summarizes current mechanistic and clinical evidence linking serum inflammatory cytokines to depression and highlights their potential as therapeutic targets in precision psychiatry.