Targeting the CCL2-CCR2 axis in depressive disorders

Abstract

Since affective disorders are considered to be underlain by the immune system malfunction, an important role in their pathophysiology is assigned to the proinflammatory mediators. Recently, chemokines, the group of chemotactic cytokines, have become a focus for basic and clinical scientists in the context of the development and treatment of brain diseases. Among them, chemokine CCL2 and its main receptor CCR2 have become candidate mediators of abnormal brain-immune system dialogue in depression. Besides the chemotactic activity, the CCL2-CCR2 axis is involved in various neurobiological processes, neurogenesis, neurotransmission, neuroinflammation, neurodegeneration, as well as neuroregeneration. Given the range of immunomodulatory possibilities that the CCL2-CCR2 pair can exert on the nervous system, its proinflammatory properties were initially thought to be a major contributor to the development of depressive disorders. However, further research suggests that the malfunctions of the nervous system are rather associated with impaired homeostatic properties manifested by the CCL2-CCR2 dyad dysfunctions. This review aims to present literature data on the action of the CCL2-CCR2 axis in the central nervous system under physiological and pathological conditions, as well as the contribution of this ligand-receptor system to the processes underlying affective disorders. Additionally, this article draws attention to the importance of the CCL2-CRR2 pathway as a potential pharmacological target with antidepressant potential.

Neuropsychiatric symptoms and seizure related with serum cytokine in epilepsy patients

“…There are increasing evidence that inflammatory mechanisms contribute to initiating or exacerbating psychiatric disorders 16 – 18 . Previous studies with major depressive disorder, schizophrenia, and generalized anxiety disorder showed that higher levels of IL-1β, IL-2, IL-6, and CCL2 were related to the severity of psychiatric symptoms 16 – 18 , 22 , 23 . However, there are only a few studies that suggested the relationship between psychiatric symptoms in epilepsy patients and inflammation.…”

“…CCL2 is a proinflammatory chemokine which causes neuroinflammation by promoting the chemotaxis of peripheral macrophages, T cells, and dendritic cells to the brain 22 , 23 . It is a possible mediator of the pathogenesis of depression since previous studies have demonstrated that serum CCL2 is elevated in major depressive disorder and reduced after antidepressant treatment 23 , 27 .…”

Dysmyelination by Oligodendrocyte‐Specific Ablation of Ninj2 Contributes to Depressive‐Like Behaviors

“…CCR2 was the receptor for Ccl2 in neurons, [ 31 ] and it is a G protein‐coupled receptor that binds G α i. [ 32 ] Recruitment of Ccl2 to CCR2 inhibited intracellular cAMP levels, which activates its downstream protein kinase A signaling pathway and plays a significant role in the development of depressive disorders. [ 33 ] Therefore, the Ccl2‐CCR2‐cAMP axis could be a potential machinery for the control of neuronal activities and the presence of depression.…”

Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection

“…Recently, chemokines have become a focus in the context of the development and treatment of brain diseases. Among them, chemokine CCL2 and its main receptor CCR2 have become candidate mediators of abnormal brain–immune-system dialogue in depression [ 19 ]. It has also been reported that an atypical chemokine receptor CCL2 binding, supports sustained inflammation and increased AD risk [ 20 ].…”