Disruption of splenic nerve‐to‐spleen neurotransmission worsens disease outcome in a murine model of systemic lupus erythematosus

Abstract

Aberrant chronic inflammation can usually be counteracted by endogenous mechanisms; however, such mechanisms may be impaired in the development of hypertension and renal injury. These anti‐inflammatory pathways involve the autonomic nervous system but it is unclear which branch is primarily responsible for quelling inflammation in chronic inflammatory conditions. The cholinergic anti‐inflammatory pathway is a compensatory mechanism thought to include a direct anatomical connection between the parasympathetic vagus and the sympathetic splenic nerve. Although this route of neurotransmission is controversial, we have evidence that stimulation of both of these nerves individually results in a decrease in the production and release of pro‐inflammatory cytokines from splenic immune cells. Our preliminary findings also indicate that chemical splenic denervation may disrupt anti‐inflammatory mechanisms, suggesting an important sympathetic component. In order to confirm this we removed the spleen from mice with systemic lupus erythematosus (SLE), a model of chronic inflammation, hypertension and renal injury, and hypothesized that splenectomy would further disrupt sympathetic neurotransmission within the cholinergic anti‐inflammatory pathway and result in worsened disease outcome. Female SLE mice were subjected to splenectomy or sham surgery (n = 10–12/group) at 31 weeks of age before being implanted with arterial catheters, blood pressure measurement and subsequently euthanization 4 weeks later. Anti‐double‐stranded autoantibodies, the hallmark of SLE, were not different amongst sham and splenectomized mice (4.8e5 ± 8.1e4 vs. 4.6e5 ± 5.4e4 activity units; p = 0.857), and neither was body weight (41.6 ± 2.0 vs. 40.1 ± 1.1 g; p = 0.497). However the incidence of albuminuria [> 300 mg/dL; 42% (5 out of 12) vs. 33% (3 out of 9)] and leukocytes in the urine [50% (6 out of 12) vs. 33% (3 out of 9)] was elevated in splenectomized SLE mice compared to sham‐operated SLE mice. Although blood pressure was not different between sham‐operated and splenectomized SLE mice (131 ± 2 vs. 134 ± 7 mmHg; p = 0.815), there was an increase in mortality following splenectomy [33% (4 out of 12) vs. 10% (1 out of 10)]. In summary, although further studies are needed to confirm the effect splenectomy on inflammation in SLE mice we found that splenectomy exacerbated the progression of SLE disease. This suggests that the sympathetic component of the cholinergic anti‐inflammatory pathway may be important in combating the inflammation in SLE. Taken together, our studies on vagus nerve stimulation, splenic nerve stimulation and denervation and splenectomy in SLE mice suggest critical interactions between autonomic branches that may be impaired during chronic inflammation. Future studies may use technology like direct vagal stimulation via central injections and designer receptors exclusively activated by designer drugs (DREADDs) to further characterize the importance of these autonomic nervous system‐mediated pathways.Support or Funding InformationFunded by NIH 1K01HL139869 and the Lupus Research Alliance Novel Disease GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.