α2-Adrenergic modulation of neuroimmune interactions differs between the spleen and mesenteric lymph nodes

The sympathetic nervous system modulates immune responses through the release of norepinephrine (NE), yet the dynamics of this signaling differ across lymphoid organs. In this study, we investigated how NE release and α2-adrenergic receptor (α2AR) modulation influence neuroimmune interactions in the spleen and mesenteric lymph nodes (MLNs), 2 secondary lymphoid tissues with distinct innervation patterns. Using fast-scan cyclic voltammetry (FSCV), we found that the spleen exhibited more frequent and higher-amplitude NE events than the MLNs, consistent with its denser sympathetic innervation. Pharmacological manipulation of α2ARs revealed that yohimbine hydrochloride, an α2AR antagonist, increased NE release in both organs, while dexmedetomidine hydrochloride, an α2AR agonist, suppressed it, often below detection thresholds. Complementary 3D immunohistochemistry demonstrated tissue- and cell type–specific changes in immune cell proximity to neuronal structures following adrenergic modulation, with T cells and B cells displaying distinct spatial reorganization. These findings highlight that α2AR signaling fine-tunes NE release and immune cell localization in a context-dependent manner, influenced by organ-specific architecture and innervation. Our results underscore the importance of dynamic local neuroimmune interactions in immune regulation and suggest potential therapeutic opportunities for targeting adrenergic signaling in inflammatory and autoimmune diseases.