The Function And Regulation Mechanism Of Purine-metabolic Disorder In CD4~+T Cells In The Onset Of Anxiety

The brain is the material basis of biological consciousness.In the brain,various nervous cells are interconnected with synaptosomes and are undergoing complex changes.Under different external stress,a series of physiological changes in the animal will eventually lead to changes in mental phenomena.Chronic physiological or psychological stress will enhance the neuroplasticity of the brain and increase the risk of depression and anxiety.Chronic stress can also cause the dysfunction of peripheral T lymphocyte.Studies have confirmed that changes in the center nervous system(CNS)are mediated by the immune system,while the specific pathological function and regulatory mechanisms of the immune system in mental illness remains poorly investigated.In this study,we found that the mice exposed to externally chronic stress displayed significant symptoms of anxiety and a significant increase in the proportion of peripheral T lymphocyte,characterized by a series of animal behavioral experiments and cell biochemical experiments.In anxious mice,the mitochondria in CD4~+ T cells are severely fragmented,which could transfer anxiety symptoms to recipient mice through adoptive transfer.Interestingly,the capacity of "anxiety" CD4~+ T cells is not affected by their activated features,suggested by EAE models and development analysis.Our data further found that the "anxious" features of CD4~+ T cells can also be obtained by depleting the mitochondrial outer membrane protein MIGA2 or MFN1 / 2,which can also be transmitted to receipt mice by adoptive transfer.We also revealed that mitochondria fragmentation in CD4~+ T cells was induced by leukotriene B4 from anxious mice,in which anxiety was relieved by removal of CD4~+ T with anti-CD4 antibody injection.These results demonstrated that externally chronic stress caused the mitochondrial fragmentation in in CD4~+ T cells,which caused some special effect on the CNS.To investigate the underlying mechanism of pathological CD4~+ T cells in regulating the CNS,we performed metabolome analysis of mouse serum and brain.The results indicated that the CD4~+ T cells with fragmented mitochondria led to purine metabolism disorders such as excessive xanthine production.The anxious features including mitochondrial fragment in CD4~+ T cells and increased xanthine content,were also detected in peripheral blood of patients with anxiety disorders.After passing the blood-brain barrier(BBB),xanthine acted on the oligodendrocytes in the left amygdala via purine receptors Ador A1,and induced the activation and proliferation of oligodendrocytes,which further promoted the activation of neurons.We have also confirmed that the hyperproduction of xanthine in CD4~+ T cells with fragmented mitochondria was accumulated IRF-1-mediated de novo synthesis from glucose,which caused by various critical enzymes related to purine synthesis.Thus,the anxious mice were recovered when preventing the synthesis of purines.This study considered the peripheral immune system and the mental system as one holistic system,and explored the mechanism of immune T cells in anxiety diseases.In this process,CD4~+ T cells with fragmented mitochondria played an essential role and provided a novel T-cell-based treatment for psychiatric diseases.