The α7 nicotinic acetylcholine receptor – a promising target for the treatment of fibrotic skin disorders

Abstract Targeting neuroendocrine receptors can be considered as another interesting approach to treat fibrotic disorders. Previously, we could demonstrate that tropisetron, a classical serotonin receptor blocker, can modulate collagen synthesis and acts in vitro via the α7 nicotinic acetylcholine receptor (α7nAchR). Here, we used a pharmacological approach with specific α7nAchR agonists to validate this hypothesis. PHA-543613, a α7nAchR-specific agonist did not only prevent but also reversed established skin fibrosis of mice injected with bleomycin. Interestingly, agonistic stimulation of α7nAchR likewise attenuated experimental skin fibrosis in the non-inflammation driven AdTBRIact mouse model indicating fibroblast-mediated and not only anti-inflammatory effects of such agents. The fibroblast-mediated effects were confirmed in vitro using human dermal fibroblasts (HDFs) in which α7nAchR-specific agonists strongly reduced the impact of transforming growth factor (TGF)-β1-mediated expression on collagen and myofibroblast marker expression. These actions were linked to modulation of the redox-sensitive transcription factor JunB and impairment of the mitochondrial respiratory system. Our results indicate that pharmacological stimulation of the α7nAchR could be a promising target for treatment of patients with skin fibrotic diseases. Moreover, our results suggest a mechanistic axis of collagen synthesis regulation via the mitochondrial respiratory system.