Formation and development of the immune inflammation hypothesis in depression

Depression has become a severe public health concern, widely recognized as a prevalent mental disorder with a high incidence rate, substantial disability burden, and a high suicide rate. Antidepressants based on the traditional monoamine hypothesis have achieved certain success in clinical application. However, this hypothesis still faces significant limitations in explaining disease heterogeneity and treatment resistance. In recent years, clinical observations and experimental studies have highlighted the growing significance of immune system dysfunction in the pathogenesis of depression, leading to the development of the immunoinflammatory hypothesis of depression. The origins of the immunoinflammatory hypothesis can be traced back to the macrophage theory of depression, which shifted the focus of depressive pathogenesis from a generalized inflammatory response to the overactivation of specific immune cells, namely macrophages. The subsequent development of the cytokine hypothesis further elucidated the role of cytokines as key messengers linking peripheral immune activation to central nervous system dysfunction. It also systematically outlined the network of pathways through which the immune system influences depressive behaviors. Recent studies have suggested that different immune subtypes, such as myeloid-dominated and lymphocytic-dominated immune activation, may be associated with distinct clinical manifestations of depression. This insight not only enriches the theoretical implications of the immunoinflammatory hypothesis but also promotes the development of inflammatory markers. The proposal of the immunoinflammatory hypothesis has, for the first time, extended the etiology of depression from the central nervous system to the peripheral immune system. Thus, the formation and development of the immunoinflammatory hypothesis, the core pathological mechanisms underlying immune inflammation-induced depression, as well as the biomarkers and treatment strategies based on this hypothesis are reviewed. This review aims to provide a theoretical framework for a deeper understanding of the immunoinflammatory mechanisms underlying depression and to promote the development of precision treatment regimens for immune-driven depression.