Norepinephrine is a novel and essential regulator for T-lymphocyte interleukin 17A expression

The longstanding association between psychological trauma or stress and subsequent chronic inflammatory disorders is well-documented, but the mechanism by which psychopathology causes these immune changes has yet to be elucidated. We have previously reported that sympathetic innervation to lymphoid organs and beta adrenergic receptor signaling are essential for T-lymphocyte interleukin 17A (IL-17A) production and T _H 17 polarization, though the exact mechanistic contribution of this signaling to the development of T _H 17 cells remained unclear. Therefore, we hypothesized that norepinephrine (NE) is a novel and direct regulator of T-lymphocyte IL-17A expression. Herein, we indeed observed that NE regulates baseline IL-17A in vivo . We further identified a novel mechanism by which transforming growth factor beta (TGFβ) and NE together result in T _H 17 polarization and IL-17A production in CD4+ T-lymphocytes. Additionally, we found that cAMP, PKA, and CREB are induced by NE signaling, which ultimately increases CBP/p300 activity to initiate RORγt transcription. Surprisingly, our data also demonstrate that STAT3, a transcription factor previously described as necessary for canonical T _H 17 polarization, is not involved in this novel pathway and may even be downregulated. Combined with bulk RNA sequencing data, our data highlight robust differences between the novel and canonical pathways to T _H 17 polarization. Altogether, our data reveal a novel, noncanonical mechanism that links sympathetic nervous system activity with IL-17A related inflammation, which may have significant relevance to sympathoexcitation-related disorders that stem from psychological trauma or stress.