In response to peripheral infections, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behavior. Prolonged activation of the immune system, such as in systemic infections, cancer, or autoimmune diseases, can lead to exacerbated sickness and depression in vulnerable individuals. Inflammation is a significant biological factor that may increase the risk of major depressive episodes, similar to traditional psychosocial factors. Sickness behavior includes symptoms like fever, fatigue, and depression, which are often overlooked but are linked to immune signaling to the brain. Pro-inflammatory cytokines such as IL-1β and TNF-α induce sickness behavior and depression in physically ill patients. Anti-inflammatory cytokines can reduce these symptoms. The brain monitors peripheral immune responses through various pathways, including afferent nerves, TLRs, and cytokine transporters. Cytokines can affect brain circuits and neurotransmitters, leading to behavioral changes. Inflammation may also contribute to depression by altering serotonin metabolism and causing neurovegetative symptoms. Animal studies show that cytokines can induce depression-like behavior, and genetic models support this. The role of tryptophan metabolism and IDO in depression is also discussed. Inflammation is linked to depression in medically ill individuals, with increased prevalence in conditions like coronary heart disease. The relationship between inflammation and depression is complex, involving immune-to-brain communication and neurobiological mechanisms. Future research aims to translate these findings into clinical applications, focusing on inflammation-targeting therapies for depression.In response to peripheral infections, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behavior. Prolonged activation of the immune system, such as in systemic infections, cancer, or autoimmune diseases, can lead to exacerbated sickness and depression in vulnerable individuals. Inflammation is a significant biological factor that may increase the risk of major depressive episodes, similar to traditional psychosocial factors. Sickness behavior includes symptoms like fever, fatigue, and depression, which are often overlooked but are linked to immune signaling to the brain. Pro-inflammatory cytokines such as IL-1β and TNF-α induce sickness behavior and depression in physically ill patients. Anti-inflammatory cytokines can reduce these symptoms. The brain monitors peripheral immune responses through various pathways, including afferent nerves, TLRs, and cytokine transporters. Cytokines can affect brain circuits and neurotransmitters, leading to behavioral changes. Inflammation may also contribute to depression by altering serotonin metabolism and causing neurovegetative symptoms. Animal studies show that cytokines can induce depression-like behavior, and genetic models support this. The role of tryptophan metabolism and IDO in depression is also discussed. Inflammation is linked to depression in medically ill individuals, with increased prevalence in conditions like coronary heart disease. The relationship between inflammation and depression is complex, involving immune-to-brain communication and neurobiological mechanisms. Future research aims to translate these findings into clinical applications, focusing on inflammation-targeting therapies for depression.