Effects of Vagus Nerve Stimulation in a Murine Model of Systemic Lupus Erythematosus
Authors: Mathis Keisa W. , Stauss Harald , Pham Grace S. , Kim Suhhyun S. , Kulp Denis V. 
Published: June 2021

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease that predominantly affects women at a ratio of 9:1 over males. Renal inflammation is prevalent in SLE and this contributes to the pathogenesis of renal injury and hypertension in the disease. In addition, there is autonomic dysfunction in SLE: increased sympathetic and decreased parasympathetic nervous system activation. The parasympathetic vagus nerve is implicated in an endogenous neuroimmune mechanism, the cholinergic anti‐inflammatory pathway, which regulates inflammation. Upon detection of increased inflammation, the efferent vagus nerve stimulates the splenic nerve to release norepinephrine. Norepinephrine then acts on the β2‐receptor‐expressing T cells in the spleen, which express choline acetyltransferase. These T cells are able to release acetylcholine, which then binds to α7‐nicotinic acetylcholine receptor‐expressing macrophages and other cytokine secreting immune cells to inhibit release of pro‐inflammatory cytokines. Given that chronic inflammation and decreased parasympathetics accompany SLE, we hypothesized that vagus nerve stimulation (VNS) using electrical implants will decrease inflammatory cytokines via accentuation of the cholinergic anti‐inflammatory pathway and protect against renal injury and development of hypertension. At 25 weeks of age, vagus nerve stimulators were chronically implanted on the right vagus nerve in 17 female NZBWF1 mice, a well‐established murine model of SLE, which were divided into VNS (n=10) and sham (n=7) groups. Only female mice were used due to the prevalence of the SLE in women. Stimulators were set to target the efferent vagus nerve (3V, 5 Hz, 800 μs, at 1 hour on/off cycles) continuously for 2 weeks. At the end of the study, tissues were collected and analyzed for inflammatory markers. Spleen weight was slightly increased in SLE/VNS mice compared to SLE/sham mice (0.11 ± 0.01 vs 0.14 ± 0.03g, respectively; P=0.210). The incidence of albuminuria, an index of renal injury measured by Albustix, was also decreased in SLE/VNS mice compared to shams (29% vs 10%). Moreover, flow cytometry indicated that SLE/VNS mice had slightly less CD3+/CD4+ bone marrow T‐cells when compared with SLE/sham mice (27.30 ± 9.41% vs 40.17 ± 7.01%; P=0.334). These results hint at possible protection following vagus nerve stimulation in SLE; however future studies are needed to determine the impact of this therapy on blood pressure. Furthermore, clinical trials (NCT02822989) are being conducted to assess the effects of VNS and cholinergic anti‐inflammatory pathway activation on musculoskeletal pain that SLE patients experience. The results from our lab will provide evidence of potential use of VNS in SLE patients to not only manage pain, but also to quell chronic renal inflammation and delay or prevent renal injury and hypertension.Support or Funding InformationFunded by an AHA Scientist Development Grant (14SDG18320033) to KWM and UNTHSC Intramural FundingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.