**Background:** Major depressive disorder (MDD) affects approximately 3.8% of the global population, with women twice as likely to develop depression compared to men (2:1 ratio). Depression is a heterogeneous disorder associated with alterations in both innate and adaptive immunity. This review synthesizes evidence for sex-specific immune mechanisms that may account for differences in depression prevalence, symptom presentation, and treatment response between men and women.
**Methods:** The authors conducted a narrative review of the literature examining sex differences in immune function as they relate to depression. They systematically covered pattern recognition receptors (PRRs), damage-associated molecular patterns (DAMPs), innate immune cells (monocytes, macrophages, neutrophils, mast cells, natural killer cells), adaptive immune cells (T cells, B cells, NKT cells), cytokines, and bioactive metals. The review integrates findings from human studies, animal models, and cell-based experiments.
**Key Results:** Multiple sex differences in immune function were identified that may contribute to depression disparities. For TLR4 signaling, testosterone decreases TLR4 expression in macrophages, reducing immune sensitivity in males. Female mice require both central and peripheral TLR4 ablation for pain cessation, whereas males only require spinal microglial ablation, suggesting supernumerary pain activation systems in females. HMGB1 release differs by sex and stimulus type: less HMGB1 was released by male mouse pulmonary endothelial cells in response to hypoxia than female cells, but mitochondrial damage triggered greater HMGB1 release in male cells. TLR7 and TLR9 expression is elevated in depressed patients and attenuated after 4 weeks of antidepressant use. Approximately 15% of people develop depression within 6 months of COVID-19 infection, with ~6% reporting first-episode depression. Women are more likely to develop long COVID. Interferon-alpha treatment for hepatitis C induced depression in 20–40% of patients. Plasmacytoid dendritic cells from women produced more IFN-α than cells from men, mediated by IFN regulatory factor 5 levels. IL-6 is repeatedly elevated in depression; higher childhood IL-6 predicts depression or psychosis in late adolescence. Social stress increases peripheral IL-6 in female mice but does not determine stress resilience or susceptibility. Monocytes from females produce 1.8 times more leukotrienes than males and express more fractalkine receptors (CX3CR1). Women have 0.66 times higher neutrophil levels than men. Leptin, which correlates with depression and mediates neutrophil migration to the brain, is higher in women due to greater adipose tissue. Approximately 70% of depressed patients also suffer from allergies. Diminished natural killer cell activity is associated with MDD, primarily in men. Depressed patients have significantly higher CD4/CD8 ratios than controls. CD4+ T cells from male mice produce more IL-17 than female cells. Preeclampsia severity predicts postpartum depression, with 44% of severe cases resulting in depression. Postpartum depression occurs in 15–20% of women and 8–10% of men. Women have lower zinc and higher copper levels, potentially contributing to higher rates of treatment-resistant depression.
**Clinical Implications:** The authors propose five refinements for studying inflammation and mood disorders: (1) take a systems approach examining patterns across multiple cell types and cytokines; (2) integrate dynamic cycles of sterile and nonsterile inflammation; (3) consider sex as a critical factor given diverse immune responses from genetics, hormones, and development; (4) adopt an RDoC approach linking specific symptoms (fatigue, appetite changes, pain, substance use, suicidal ideation) to immune function rather than disease categories; and (5) screen for immune alterations early in life to limit neuroinflammatory damage. The review emphasizes that there is no single cytokine or immune cell responsible for depression, and that men and women would likely need different immune-based therapies. The authors call for improved reporting of sex in study methods and inclusion of sufficient females in both human and animal studies to enable sex-difference analyses.