Biology subjects

deRoos, P.

Publications and source records attributed to deRoos, P..

3 recordsLinked to original sources

bioRxiv2024

Damage-induced IL-18 stimulates thymic NK Cells limiting endogenous tissue regeneration

Interleukin-18 is an acute phase pro-inflammatory molecule crucial for mediating viral clearance by activating Th1 CD4+, cytotoxic CD8+ T, and NK cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18 stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures restoration of immune competence after acute insults like stress, infection, chemotherapy, and radiation. NK cells suppressed thymus recovery by aberrantly targeting thymic epithelial cells (TECs), which act as the master regulators of organ function and regeneration. Together these studies reveal a novel pathway regulating tissue regeneration in the thymus and offer IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy for its capacity to elicit a type-1 immune response, these findings also offer insight into potential off-target effects.

immunology↗

bioRxiv2023

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

immunology↗

bioRxiv2021

Activation of the Zinc-sensing receptor GPR39 promotes T cell reconstitution after hematopoietic stem cell transplant

Prolonged lymphopenia represents a major clinical problem after cytoreductive therapies such as chemotherapy and the conditioning required for hematopoietic stem cell transplant (HCT), contributing toward the risk of infections and malignant relapse. Restoration of T cell immunity is dependent on tissue regeneration in the thymus, the primary site of T cell development; although the capacity of the thymus to repair itself diminishes over lifespan. However, although boosting thymic function and T cell reconstitution is of considerable clinical importance, there are currently no approved therapies for treating lymphopenia. Here we found that Zinc (Zn), is critically important for both normal T cell development as well as repair after acute damage. Accumulated Zn in thymocytes during development was released into the extracellular milieu after HCT conditioning, where it triggered regeneration by stimulating endothelial cell-production of BMP4 via the cell surface receptor GPR39. Dietary supplementation of Zn was sufficient to promote thymic function in a mouse model of allogeneic HCT, including enhancing the number of recent thymic emigrants in circulation; although direct targeting of GPR39 with a small molecule agonist enhanced thymic function without the need for prior Zn accumulation in thymocytes. Together, these findings not only define an important pathway underlying tissue regeneration, but also offer an innovative preclinical approach to treat lymphopenia in HCT recipients. KEY POINTSO_LIThymocytes release zinc after HCT conditioning is sensed by GPR39 and promotes epithelial repair C_LIO_LIPharmacologic stimulation of GPR39 promotes T cell reconstitution after HCT C_LI

immunology↗