Damage-induced pyroptosis drives endogenous thymic regeneration viainduction of Foxn1 by purinergic receptor activation

Endogenous thymic regeneration is a crucial process that allows for the renewal of immune competence following stress, infection or cytoreductive conditioning. Fully understanding the molecular mechanisms driving regeneration will uncover therapeutic targets to enhance regeneration. We previously demonstrated that high levels of homeostatic apoptosis suppress regeneration and that a reduction in the presence of damage-induced apoptotic thymocytes facilitates regeneration. Here we identified that cell-specific metabolic remodeling after ionizing radiation steers thymocytes towards mitochondrial-driven pyroptotic cell death. We further identified that a key damage-associated molecular pattern (DAMP), ATP, stimulates the cell surface purinergic receptor P2Y2 on cortical thymic epithelial cells (cTECs) acutely after damage, enhancing expression of Foxn1, the critical thymic transcription factor. Targeting the P2Y2 receptor with the agonist UTP{gamma}S promotes rapid regeneration of the thymus in vivo following acute damage. Together these data demonstrate that intrinsic metabolic regulation of pyruvate processing is a critical process driving thymus repair and identifies the P2Y2 receptor as a novel molecular therapeutic target to enhance thymus regeneration. SUMMARYO_LIThymocytes rapidly and transiently undergo pyroptosis after acute thymic damage and promote regeneration. C_LIO_LIDamage-induced redirection of pyruvate acutely enhances mitochondrial OXPHOS in thymocytes. C_LIO_LIElevated mitochondrial ROS promotes pyroptosis in thymocytes after acute insult by driving caspase 1 cleavage. C_LIO_LIExtracellular ATP release promotes Foxn1 expression in cTECs via activation of P2Y2 C_LIO_LITherapeutic targeting of the P2Y2 receptor promotes thymic regeneration. C_LI