Authors
Natour, T., Lauten, T. H., Pitts, L. J., Reed, E. C., Giebel, K. R., Case, A. J.
Abstract
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 TH17 polarization, though the exact mechanistic contribution of this signaling to the development of TH17 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 (TGF{beta}) and NE together result in TH17 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 ROR{gamma}t transcription. Surprisingly, our data also demonstrate that STAT3, a transcription factor previously described as necessary for canonical TH17 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 TH17 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.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 25 Aug 2026.
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