Cellular therapies Nervous system regulates thymic regeneration after immune injuries

Paradoxical to its importance as the main organ responsible for generating T cells throughout life, the thymus is extremely sensitive to negative insults including cytoreductive chemoor radiation therapy, infections and GVHD. Insufficient recovery of thymic function has been directly correlated with increased risk of opportunistic infection and poor clinical outcome in transplanted recipients. Therefore, strategies to regenerate thymic function and immune reconstitution represent a significant unmet clinical need. While multiple paracrine and endocrine pathways have been shown to regulate thymic function, the regulatory role of the peripheral nervous system remains largely unknown. Given its previously described role in modulating bone marrow hematopoiesis after damage, we sought to investigate if the sympathetic nervous system (SNS) mediated similar effects on thymic regeneration after immune insults. We observed that thymic concentration of epinephrine and norepinephrine was increased in mice after sub-lethal total body irradiation (SLTBI), reaching a maximum concentration at day 4 and returning to its baseline levels at day 14 post-SLTBI. Daily administration of epinephrine or norepinephrine directly resulted in a significant decrease in thymic regeneration post-SLTBI. We identified that SNS-related negative regulation of thymic recovery occurs specifically through an α1A/D dependent mechanism, given that administration of tamsulosin, an α1A/D specific inhibitor was able to enhance thymic cellularity post-SLTBI, while no effect was observed after the administration of pan-α and pan-β adrenergic antagonists. Besides the autonomic nervous system, sensory nociceptive C-fibers have been shown to pose a strong peripheral input to the immune system, mainly via the transient receptor cation channels TRPV1 and TRPA1, which among others, serve as receptors for multiple endogenous and exogenous reactive ligands. We obsverved that whithin the thymus TRPA1 was highly expressed in the medulla and sparsely in the cortex, mainly representing intraparenchymal small nerve fibers. Nerve fibers were also found to adjacent to vessels, while interestingly thymic endothelial cells expressed TRPA1 as well. On the other hand, TRPV1 expression was weak and primarily localized at the subcortical area. While thymic cellularity was unimpaired in a TRPV1 KO setting, TRPA1 KO mice exhibited significantly lower thymic cellularity at baseline and after SLTBI, suggesting that TRPA1 represents a critical factor for organ regeneration after insults. Consistenlty, administration of cinnamaldehyde and allyl-isothiocyanate, two potent, exogenous TRPA1 agonists, significantly enhanced thymic regeneration post-SLTBI. Our study attributes for the first time functional roles to distinct peripheral nervous system compartments in the context of endogenous thymic regeneration. Most importantly, the pharmacological modulation of negative SNS-imposed or positive TRPA1/nociceptive-imposed signals represents a novel therapeutic approach to enhance thymic regeneration and immune recovery in immunocompromised patients. Disclosure of conflict of interest