Xathine unveiled: Bridging CD4+ T cell and stress-induced disorders through purine metabolism

Abstract

Neuroimmunology, a field exploring the intricate interplay between the nervous and immune systems, has long focused on the regulatory effects of stress on immune function. Chronic stress activates the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary system, leading to glucocorticoid and catecholamine release, which modulate T cell activity. Clinical studies reveal that chronic stress dysregulates peripheral T cells, particularly reducing CD4⁺ T cell counts, which are implicated in anxiety and obsessive-compulsive disorders. The current research demonstrates that chronic stress depletes peripheral CD4⁺ T cells, and their depletion protects against stress-induced anxiety-like behaviors. Furthermore, adoptive transfer of CD4⁺ T cells from anxious mice induces anxiety in recipient mice, highlighting the pivotal role of these cells in stress-related disorders. This finding uncovers a novel mechanism where stress triggers purine metabolism dysregulation in CD4⁺ T cells, leading to elevated xanthine and adenine levels. Xanthine enhances amygdala neuronal activity, contributing to anxiety-like behaviors, while adenine suppresses it. Stress-induced leukotriene B4 promotes mitochondrial fission in CD4⁺ T cells, enhancing IRF1 nuclear accumulation and upregulating purine synthesis enzymes, resulting in xanthine overproduction. This metabolic shift links mitochondrial dysfunction to stress-induced anxiety. Purines exert their effects via adenosine receptors, with A1 in oligodendrocytes mediating xanthine-induced neuronal activation in the brain. In the gut, stress-induced xanthine elevation activates A2B receptors, driving exosome biogenesis and contributing to irritable bowel syndrome pathogenesis. These findings identify dysregulated purine metabolism in CD4⁺ T cells as a hallmark of stress-related disorders, offering novel therapeutic targets. Purine synthesis inhibitors and adenosine receptor antagonists show promise in alleviating anxiety and IBS symptoms, paving the way for innovative treatments for stress-induced diseases. This research bridges neuroimmunology and metabolism, providing a comprehensive understanding of stress-related disorders and their therapeutic potential.