Stress hormones collaborate to induce lymphocyte apoptosis after high level spinal cord injury.
Post-traumatic immune suppression renders individuals with spinal cord injury (SCI) susceptible to infection. Normally, proper immune function is regulated by collaboration between the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis and involves the controlled release of glucocorticoids (GCs) and norepinephrine (NE). Recently, we showed that after high thoracic (T3) SCI, aberrant levels of GCs and NE accumulate in the blood and spleen, respectively. These changes are associated with splenic atrophy, splenic leucopenia, increased intrasplenic caspase 3 levels, and suppressed B lymphocyte function. As GCs boost SNS function, in part by increasing the expression and affinity of beta2 adrenergic receptors (beta2ARs) while simultaneously preventing beta2AR down-regulation, we predicted that surges in stress hormones (i.e., GCs and NE) in the blood and spleen of mice with high-level SCI would act concurrently to adversely affect lymphocyte function and survival. Here, we show that post-SCI concentrations of GCs enhance the sensitivity of lymphocytes to beta2AR stimulation causing an increase in intracellular Bcl-2 interacting mediator of cell death (Bim) and subsequent apoptosis. In vivo, the combined antagonism of GC receptors and beta2ARs significantly diminished lymphocyte Bim levels and SCI-induced splenic lymphopenia. Together, these data suggest that pharmacological antagonists of the HPA/SNS axes should be considered as adjunct therapies for ameliorating post-traumatic immune suppression in quadriplegics and high paraplegics.
Lucin
Kurt M
KM
Department of Molecular Virology, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Sanders
Virginia M
VM
Popovich
Phillip G
PG
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005260:Female; D006728:Hormones / Q000097:blood / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D007165:Immunosuppression Therapy; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D013119:Spinal Cord Injuries / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013312:Stress, Physiological / Q000276:immunology*; D013564:Sympathetic Nervous System / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D013904:Thoracic Vertebrae
D006728:Hormones