Cholinergic anti-inflammatory pathway activity in dialysis patients: a role for neuroimmunomodulation?

Abstract

BackgroundThe cholinergic anti-inflammatory pathway (CAP) modulates inflammatory responses through the vagus nerve and the α-7-nicotinic acetylcholine receptor (α7nAChR) on macrophages and immune cells. Sympathetic/parasympathetic imbalance and chronic inflammation are both linked to poor outcome in dialysis patients. The aim of this study was to investigate CAP activity in these patients.MethodsTwenty dialysis patients, 12 hemodialysis (HD) and 8 peritoneal dialysis (PD) patients (12 male, 8 female; age range 47–83 years) and 8 controls (5 male, 3 female; age range 31–52 years) were analyzed for C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin-1b (IL-1b), IL-6 and IL-10 at baseline. The cytokines were then assessed after whole blood stimulation ex vivo with lipopolysaccharide (LPS) (10 and 100 ng/mL) and again in the presence of 45 and 90 μmol/L GTS-21, a cholinergic α7nAChR agonist.ResultsCRP, TNF, IL-1 and IL-6 were significantly higher, whereas IL-10 was significantly lower at baseline in patients compared with controls. After LPS stimulation, TNF increased significantly more in patients than in controls but decreased to similar levels in both groups after addition of GTS-21. IL-6 attenuation was comparable with TNF and the IL-1b pattern was similar but remained significantly higher in patients. Interestingly, IL-10 increased after GTS-21 in a dose-dependent manner, but only in patients. Results in HD and PD patients did not differ.ConclusionsThe response of immune cells after LPS exposure and cholinergic stimulation suggests a functional CAP in dialysis patients. It may thus be possible to target the α7nAChR control of cytokine release as an anti-inflammatory strategy and thereby improve outcome in these patients.

The cholinergic anti-inflammatory pathway in chronic kidney disease—review and vagus nerve stimulation clinical pilot study

“…This pathway has been investigated in clinical studies of inflammatory diseases. We and others have shown that vagal tone is significantly decreased and associated with inflammatory markers in RA, IBD and dialysis patients [ 127 , 133 , 134 ]. Recent and ongoing research further expands the prospects of modulating the CAP and future therapeutic possibilities.…”

“…We have previously shown that dialysis patients have a functional CAP ex vivo [ 127 ]. However, in our pilot VNS study we could not demonstrate significant alterations in cytokine levels.…”

“…HRV measurements validated results from previous studies demonstrating autonomic dysfunction in dialysis patients. We concluded that dialysis patients, despite autonomic dysfunction and an underlying dysregulated cytokine response, have a functional CAP [ 127 ].…”

“…Whole blood was stimulated with LPS 10 and 100 ng/mL and GTS-21 90 µmol/L using a method previously described and used in our study of CAP functionality in dialysis patients [ 127 ]. After 4 h incubation at 37°C on a rocking platform, plasma was collected by centrifugation (2600 g , 20 min, 18°C, Eppendorf centrifuge 5804 R) and frozen at −80°C pending cytokine analyses.…”

The cholinergic anti-inflammatory pathway in resistant hypertension treated with renal denervation

“…The whole blood assay, a standard method to test cholinergic function, was performed by a method previously described (Bruchfeld et al, 2010; Hilderman et al, 2015). In brief, whole blood was collected in heparinized tubes and immediately kept in a 37 °C heated container until processed after 60–120 min.…”