Acute stress-induced thymic atrophy is mediated by intrathymic inflammatory and wound healing responses (113.25)

Abstract

Abstract Productive 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, and irradiation or immunosuppressive therapies. Little is known, however, about intrathymic mechanisms that may actively contribute to thymus atrophy or initiate thymic recovery following stress events. In this work, phenotypic, histologic and transcriptome/pathway analysis was performed to identify putative intrathymic mechanisms that drive endotoxemia-induced involution of murine thymic tissue. 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. Taken together, these observations demonstrated that both systemic and direct intrathymic responses to endotoxin challenge concurrently contribute to thymic involution during endotoxemia.