Both the autonomic nervous system and the immune system have been implicated in hypertension. Because of the bidirectional communication between the two systems, there is recent interest in neuro-immune mechanisms that may also play a role in the pathogenesis of the disease. Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with aberrant immune function and chronic inflammation that contributes to the prevalent hypertension. SLE is also associated with prevalent autonomic dysfunction; therefore, SLE is an ideal model to study the link between the nervous system, immune system and hypertension. The cholinergic anti-inflammatory pathway is a vagally-mediated neuro-immune mechanism that suppresses the production and secretion of cytokines from splenic immune cells upon stimulation. The α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) on these splenic immune cells is a critical component of the cholinergic anti-inflammatory pathway. Although stimulation of this pathway has been shown to be protective in chronic inflammatory diseases, it is unknown whether this novel neuro-immune pathway is important in hypertension. Our overall hypothesis is that the cholinergic anti-inflammatory pathway is impaired in hypertension and that activation of this pathway at the level of the α7nAChR would protect from the development of the disease. To test this hypothesis we measured splenic protein expression of α7nAChR and the vesicular acetylcholine transporter (VAChT) in female SLE mice with hypertension. SLE (NZBWF1) mice had 365±30% higher splenic protein expression of α7nAChR compared to control NZW mice (0.038±0.002 vs. 0.008±0.003; n ≤ 3; p<0.001). Similarly, splenic protein expression of VAChT was 24.4±7.6% higher in SLE mice compared to controls (0.33±0.02 vs. 0.26±0.03; n ≤ 3; p=NS). These data suggest the cholinergic pathway may be impaired at the level of the α7nAChR in SLE mice. In order to investigate whether activation of the pathway is protective in SLE hypertension, female SLE and control mice were infused with nicotine hydrogen tartrate salt (2 mg/kg/day, SC) or saline for 7 days. Splenic protein expression of TNF-a and IL-6 was significantly higher in saline-treated SLE mice compared to nicotine-treated SLE mice (1.37±0.06 vs. 1.09±0.06 and 0.55±0.10 vs. 0.36±0.04; n = 3; all p<0.05), suggesting efficacy of the therapy in reducing splenic inflammation. Mean arterial blood pressure was increased in SLE mice compared to controls (140±4 vs. 114±2; n = 6-9; p<0.001). Nicotine prevented the rise in MAP in SLE mice (129±4; p=0.022), but did not alter MAP in controls (121±3). This protection from hypertension coincided with a 17±5% reduction (p=0.041) in renal TNF-α in nicotine-treated SLE mice (n=3), which is important because we have shown that renal TNF-α plays a mechanistic role in the development of hypertension during SLE. Because nicotine acts on both ganglionic and peripheral cholinergic receptors, in a subsequent study mice were administered the selective α7nAChR agonist, PNU-282987 (0.38 mg/kg/day, IP), or vehicle for 28 days. Splenic protein expression of TNF-α and IL-6 was significantly higher in saline-treated SLE mice compared to PNU-282987-treated SLE mice (0.54±0.03 vs. 0.33±0.01 and 0.86±0.05 vs. 0.40±0.08; n = 3; all p<0.05). MAP was increased in SLE mice compared to controls (138±2 vs. 122±5; n ≤ 5). PNU-282987 prevented the rise in MAP in SLE mice (128±4), but did not alter MAP in controls (125±5). These data suggest the anti-inflammatory effects of cholinergic agonists may protect from SLE hypertension. Taken together, the cholinergic anti-inflammatory pathway, particularly the α7nAChR in the spleen, may be an important target in patients with hypertension and other diseases of chronic inflammation.