Preprint Alpha7 nicotinic acetylcholine receptor agonist PHA 568487 dampens inflammation in PBMCs from patients with coronary artery disease, 2024, Mjörnstedt+

[SNT Gatchaman]

Alpha7 nicotinic acetylcholine receptor agonist PHA 568487 dampens inflammation in PBMCs from patients with newly discovered coronary artery disease.
Filip Mjörnstedt; Rebecka Wilhelmsson; Marcus Ulleryd; Maria Hammarlund; Göran Bergström; Anders Gummesson; Maria E Johansson

BACKGROUND
The alpha7 nicotinic acetylcholine receptor α(7nAChR) controls inflammation in experimental models. The α7nAChR is expressed in human peripheral blood mononuclear cells (PBMCs) as well as in human atherosclerotic plaques, yet, its role in regulating inflammation in patients with cardiovascular disease remains unknown. In this study we aim to investigate whether stimulation of the α7nAChR can dampen the immune response in patients with newly discovered coronary artery disease (CAD).

METHODS
Human peripheral blood mononuclear cells (PBMCs) extracted from patients with verified CAD (n=38) and control participants with healthy vessels (n=38) were challenged in vitro with lipopolysaccharide (LPS) in combination with α7nAChR agonist PHA 568487. Supernatants were analyzed for cytokines using multiplex immunoassay. The CAD group was re-examined after 6 months.

RESULTS
α7nAChR stimulation decreased TNF-α in all groups, in control participants and in CAD patients, both at the first visit as well as the follow-up visit after 6 months. The most pronounced effect of α7nAChR stimulation was seen in CAD patients at their first visit, where 12 of 17 cytokines were decreased (TNF, IL-1β, IL-2, IL-4, IL-5, IL-7, IL-10, IL-17A, GM-CSF, MCP-1, MIP-1β and IL12(p70)).

CONCLUSIONS
Stimulation of α7nAChR dampens the inflammatory response in human PBMCs. This suggests that the anti-inflammatory properties of the α7nAChR may have a role in treating CAD.


Link | PDF (Preprint: MedRxiv) [Open Access]

 

[SNT Gatchaman]

after six months of statin treatment, the anti-inflammatory effect of α7nAChR stimulation was reduced. [...] These findings implicate that statins influence the inflammatory response. Indeed, statins not only reduce LDL levels in patients, but also inflammation by lowering the inflammatory biomarker hsCRP. Furthermore, statins can suppress cytokine secretion from PBMCs; in hyperlipidemic patients, simvastatin treatment reduced secretion of IL-1β from PBMCs. Intriguingly, the effect of α7nAChR stimulation is diminished after statin treatment. This lack of effect may be due to shared signaling pathways between the two, as both statins and α7nAChR agonists have been suggested to exert their anti-inflammatory effects by reducing the activity of the transcription factor nuclear factor-κB. Another possibility is that statins could alter the expression level of α7nAChR9.