CX3CL1–CX3CR1 axis promotes restraint stress-induced thymic involution through macrophage-mediated thymocyte apoptosis

Background Stress-induced thymic involution is characterized by rapid thymocyte loss and is largely attributed to glucocorticoid signaling. However, the local immune mechanisms involved remain unclear. We investigated the role of the CX3CL1–CX3CR1 axis in restraint stress (RS)-induced thymic involution. Methods Wild-type (WT) and Cx3cr1 -deficient mice were subjected to repeated RS. Thymic morphology, CX3CL1/CX3CR1 expression, apoptosis-related pathways, and stress-related hormonal responses were examined. The effects of CX3CL1 on corticosterone (CORT)-induced thymocyte apoptosis in vitro and exogenous CORT administration in vivo were also evaluated. Results RS increased CX3CL1 and CX3CR1 expression in thymic F4/80-positive macrophages. Cx3cr1 deficiency markedly attenuated RS-induced thymic involution, preserved thymic architecture, and reduced thymocyte apoptosis. RS-induced Fas ligand expression in thymic macrophages and caspase-3 activation in the thymic cortex were also attenuated by Cx3cr1 deficiency. CX3CL1 did not enhance CORT-induced thymocyte apoptosis in vitro , and a single CORT administration did not reproduce the marked thymic involution induced by repeated RS. CX3CR1 expression was also detected in hypothalamic microglia. Conclusion CX3CL1–CX3CR1 signaling contributes to RS-induced thymic involution through CX3CR1-dependent mechanisms involving macrophage-associated FasL-mediated thymocyte apoptosis and modulation of the corticosterone response, suggesting coordinated local immune and neuroendocrine mechanisms underlying stress-induced thymic involution.