Effect of Acute Bilateral Vagotomy on Tissue-Specific Inflammation in a Murine Model of Systemic Lupus Erythematosus
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Effect of Acute Bilateral Vagotomy on Tissue-Specific Inflammation in a Murine Model of Systemic Lupus Erythematosus Shyam Vedantam, Grace S Pham, Keisa W Mathis Purpose: Chronic inflammation has been implicated in the pathogenesis of hypertension. We use a model of systemic lupus erythematosus (SLE) to study this relationship since SLE is a chronic autoimmune inflammatory disorder with a high prevalence of renal injury and hypertension. SLE is also associated with diminished autonomic (vagal) tone, and this implicates impaired neuroendocrine/neuroimmune mechanisms. One example is the classic hypothalamic-pituitary-adrenal (HPA) axis, which can be activated by the afferent vagus nerve and result in cortisol production and anti-inflammatory effects. Another example is the cholinergic anti-inflammatory pathway, an endogenous vagus nerve-to-spleen pathway that reduces inflammation upon stimulation. It is thought that both of these mechanisms are dysregulated and promote chronic inflammation in SLE. To confirm the importance of the vagus nerve in regulating inflammation though these mechanisms, we performed chronic unilateral vagotomy in SLE mice and determined that this paradoxically decreased inflammatory markers in the spleen and the kidney. We hypothesized that the other vagus nerve compensated and upregulated an anti-inflammatory response and that total vagotomy would exacerbate splenic and renal inflammation. Methods: In the current study, anesthetized female SLE (NZBWF1) and control (NZW) mice (35 weeks of age; n=3 mice/group) underwent bilateral vagotomy and were euthanized 3 hours later, followed by tissue harvest. Results: Spleen tumor necrosis factor (TNF)-a (measured by Western blot and normalized to total protein) was increased in SLE mice compared to controls (4.0e6 ± 2.2e6 vs. 1.5e6 ± 3.3e5; P=NS). Acute bilateral vagotomy exacerbated this inflammation in SLE mice (5.1e6 ± 2.5e6) and controls (3.2e6 ± 6.8e5). Renal cortical TNF-a was not different in SLE and control mice (7.4e5 ± 1.6e5 vs. 6.9e5 ± 4.8e4); however, acute bilateral vagotomy exacerbated TNF-a in SLE mice (1.3e6 ± 7.2e4 vs) and controls (1.2e6 ±6.5e5). Conclusions: These findings suggest that the vagus nerve and vagally-mediated anti-inflammatory mechanisms like the HPA axis and the cholinergic anti-inflammatory pathway are critical in controlling inflammation in SLE. Future studies involving chronic bilateral vagotomy in SLE mice are necessary to confirm our hypotheses.