Vagal innervation limits brain injury by inhibiting gut-selective integrin-mediated intestinal immunocyte migration in intracerebral hemorrhage

Rationale: The vagus nerve, which connects the brain and gastrointestinal tract, helps to maintain immune balance in the intestines. Gut-specific integrins, on the other hand, help to keep immune cells in the intestines. Since immune cells from outside the intestines can significantly affect the outcome of strokes, we investigated how immune cells from the intestines affect the immune response in the brain during intracerebral hemorrhage (ICH). Methods: We aimed to examine the impact of vagal innervation on intestinal immunocyte trafficking and its influence on ICH outcomes using Kikume Green-Red (KikGR) and wildtype (WT) mice, with or without prior subdiaphragmatic vagotomy (SDV). Furthermore, we sought to elucidate the regulatory effects of vagal innervation on intestinal immunocyte trafficking by activating α7 nicotinic acetylcholine receptors (α7nAChR) in WT mice that underwent ICH after SDV. Additionally, we explored the potential intermediary role of gut-selective integrins in cholinergic transmitters-mediated intestinal immunocyte trafficking. Our methodology encompassed in vivo fluorescence imaging, flow cytometry, Western blotting, immunofluorescence staining, histopathology, and behavioral assessments to evaluate the outcomes. Results: Our findings reveal that during the acute phase of ICH, intestinal immunocytes migrated to various anatomical locations, including the circulation, hemorrhagic brain, meninges, and deep cervical lymph nodes. Pertinently, SDV resulted in diminished expression of α4β7 and αEβ7 integrins on immunocytes, leading to heightened intestinal immunocyte trafficking and exacerbated ICH outcomes. Conversely, the administration of α7nAChR agonists countered the adverse effects of vagotomy on α4β7 and αEβ7 integrin expression, thereby constraining the migration of immune cells from the intestines after ICH. The implication of α4β7 and αEβ7 integrins in this setting was supported by the ineffective influence of α7nAChR agonists on the trafficking of intestinal immunocytes enhanced by administering beta-7 integrin antagonists, such as etrolizumab. It was further supported by the exacerbated ICH outcomes by administering beta-7 integrin antagonists like etrolizumab alone. Conclusion: The identification of vagus nerve-mediated modulation of α4β7 and αEβ7 integrin expression in the trafficking of immune cells within the intestinal tract holds significant implications. This discovery presents new opportunities for developing therapeutic interventions for ICH and stimulates further investigation in this area.