Abstract
BackgroundProductive thymopoiesis is essential for a robust and healthy immune system. Thymus unfortunately is acutely sensitive to stress resulting in involution and decreased T cell production. Thymic involution is a complication of many clinical settings, including infection, malnutrition, starvation, and irradiation or immunosuppressive therapies. Systemic rises in glucocorticoids and inflammatory cytokines are known to contribute to thymic atrophy. Little is known, however, about intrathymic mechanisms that may actively contribute to thymus atrophy or initiate thymic recovery following stress events.Methodology/Principal FindingsPhenotypic, histologic and transcriptome/pathway analysis of murine thymic tissue during the early stages of endotoxemia-induced thymic involution was performed to identify putative mechanisms that drive thymic involution during stress. Thymus atrophy in this murine model was confirmed by down-regulation of genes involved in T cell development, cell activation, and cell cycle progression, correlating with observed phenotypic and histologic thymus involution. Significant gene changes support the hypothesis that multiple key intrathymic pathways are differentially activated during stress-induced thymic involution. These included direct activation of thymus tissue by LPS through TLR signaling, local expression of inflammatory cytokines, inhibition of T cell signaling, and induction of wound healing/tissue remodeling.Conclusions/SignificanceTaken together, these observations demonstrated that in addition to the classic systemic response, a direct intrathymic response to endotoxin challenge concurrently contributes to thymic involution during endotoxemia. These findings are a substantial advancement over current understanding of thymus response to stress and may lead to the development of novel therapeutic approaches to ameliorate immune deficiency associated with stress events.
Highlights
Ongoing and productive thymopoiesis is essential for development and maintenance of a robust and healthy immune system
T cell antigen receptor (TCR) alpha and beta genes (Tcra, Tcrb-j), and mRNA for T cell surface molecules CD3 epsilon, CD4, CD28, CD2, and LFA-1 (Itgal, Itgb2) were significantly lower in the atrophic thymus (Figures 4 and 5, Table S2). These analyses suggested a mechanism for decreased TCR signaling which may contribute to thymocyte apoptosis characteristic of atrophic thymus tissue
Within hours endotoxin challenge activated a systemic and intrathymic pro-inflammatory cytokine cascade which resulted in losses of thymic cellularity, TCRa gene rearrangement, and double positive (DP) thymocyte distribution
Summary
Ongoing and productive thymopoiesis is essential for development and maintenance of a robust and healthy immune system. Many factors have a negative effect on thymopoiesis and acute thymic atrophy is a complication among a variety of clinical settings, including bacterial infection [1], starvation [2], and irradiation or immunosuppressive therapies [3]. About intrathymic mechanisms that may actively drive thymus involution in response to stress. By defining intrathymic mechanisms driving thymic atrophy and tissue recovery, potential therapies could be developed to help accelerate thymic recovery and immune reconstitution. Thymic involution is a complication of many clinical settings, including infection, malnutrition, starvation, and irradiation or immunosuppressive therapies. About intrathymic mechanisms that may actively contribute to thymus atrophy or initiate thymic recovery following stress events
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
