The Non-neuronal Cholinergic System of Human Skin bits [7] and today, ACh production and expression of its receptors have been shown in a wide variety of organisms from protozoa and plants to humans, thus supporting the hypothesis that ACh is a universal cytotransmitter which has only secondarily become specialized in the nervous system. In humans, different tegumental cells covering the inner and outer surfaces of the human body and most notably various immune cells are part of the non-neuronal cholinergic system [8]. The non-neuronal cholinergic system has been implicated in numerous functions in the skin such as growth and differentiation, adhesion and motility, barrier formation, sweat and sebum secretion as well as modulation of the microcirculation. An important role in human disease, especially in infl ammatory disorders such as acne vulgaris or atopic eczema is emerging together with a wealth of new data on its physiological role in maintaining skin homeostasis [4, 9]. In human skin both resident and transiently residing cells are part of this system, creating a highly complex and interconnected cosmos in which ACh is the main player with regulatory roles in both physiology and pathophysiology [10]. The aim of this review is to provide insights into basic mechanisms of ACh action

This supports the idea that the cholinergic system is dysregulated independently from inflammation in AD and that inflammation further modulates individual nAChR subunits.

Nociceptive primary afferent neurons carry nicotinic acetylcholine receptors (nAChRs). Using RTPCR, mRNAs for all alpha-subunits have been identified in rat dorsal root ganglia (DRG) (Genzen et al., 2001; Lips et al., 2002), but the responses of nociceptive neurons to nicotine are not uniform and the cellular distribution of nAChRs within DRG, in general, and among functionally different subtypes of primary afferent neurons, in particular, are only partially resolved (Rau et al., 2005). These diverse actions might suggest the presence of various nAChR isoforms that are operative under different conditions. The present study was aimed to extend previous studies on nAChRs that contain subunits alpha4, alpha7, and alpha10 in providing data for alpha3- and alpha5-subunit-containing nAChRs (Haberberger et al., 2004; Papadopolou et al., 2004). To this end, calcium-imaging and double-labeling immunofluorescence with nAChR alpha-subunit-specific antibodies, in combination with markers for nociceptive neurons (TRPV1, I-B4), were applied.

Extraneuronal acetylcholine (ACh) has been demonstrated to influence a plethora of cutaneous cell functions in an autocrine, paracrine and endocrine fashion. Previously, we could demonstrate a differentiation‐specific expression of its nicotinic (nAChR) and muscarinic receptors (mAChR) in human epidermis and its adnexal structures including sebaceous glands. Using an immortalized human sebaceous gland cell line (SZ95 sebocytes), we examined the AChR expression pattern in vitro. In proliferating and confluent SZ95 sebocytes, a wide range of AChR subunits could be detected using RT‐PCR. In particular, we detected mRNA coding for the α3, α5, α6, α7, α10, β1, β2 and β4 nAChR as well as the M1, and M3−5. The α1 and M2 and M5 subunits could only be detected in confluent SZ95 sebocytes, while in proliferating ones these subunits remained negative. The α2, α4, α9 and β3 nAChR could not be detected. Using functional assays, we assessed the impact of cholinergic agonists and antagonists on sebocyte proliferation and differentiation as evidenced by lipid production. Atropine (inhibition of all mAChR) and himbacine (inhibition of M2 and M4) potently inhibited SZ95 sebocyte proliferation in a dose‐dependent manner with a maximum effect at milimolar concentrations, while glycopyrrolate (inhibition of M1 and M3) inhibited proliferation only at high concentrations (100 µM). Interestingly also muscarine inhibited SZ95 sebocyte proliferation, however, with a maximum effect (50%) at nanomolar concentrations. The inhibitory effect of mecamylamine was less pronounced (20%). Nicotine strongly induced SZ95 sebocyte proliferation to more than 200% in a dose‐dependent manner. Lipid production was increased by nicotine and muscarine in the micromolar range. Inhibition of nAChR by mecamylamine did not significantly influence lipid production, while even nanomolar concentrations of atropine significantly increased lipid production. In conclusion, we could demonstrate highly potent effects of the cholinergic system on sebocyte proliferation and lipid production in vitro, mediated by wealth of different AChR subunits present at least at the mRNA level. In particular, promotion of sebocyte proliferation seems to be an attractive explanation for the exacerbation of sebaceous gland–related disorders like acne under the influence of chronic nicotine ingestion. In addition, seborrhea observed after treatment with anticholinergic drugs is well in line with an increase in lipid production that we found after treatment of sebocytes with atropine.

In previous studies, high levels of acetylcholine (ACh) have been reported in psoriasis lesions. In addition, patients with guttate psoriasis respond to oral treatment with atropine. We wanted to know how the cutaneous cholinergic system could be involved in this process. Since mast cells (MC) are characteristic components of the inflammatory infiltrate of guttate psoriasis, we compared ACh receptor (AChR) composition and ACh production in both epidermis and mast cells of 10 patients with guttate psoriasis in involved and uninvolved skin on protein level using immunofluorescence and in a MC line (HMC‐1) using PCR. We could confirm the presence of numerous MC in guttate psoriasis lesion. Both in vivo and in vitro, MC lacked expression of cholinacetyltransferase (ChAT), vesicular acetylcholintransorter (VAChT) and cholintransporter‐1 (ChT‐1) but contained high levels of acetylcholinesterase (AChE). In mast cells of both involved and uninvolved skin we found both nicotinic (α3, α5, α7, α9, α10, β2 and β4 subunits) and muscarinic (M1, M3, M4, M5) AChR. In HMC‐1 cells all AChR subunits found in skin where present on mRNA level, except α7 and β2. In lesional epidermis both ACh production and AChR expression was shifted from the basal to the suprabasal layers especially the nicotinic α3, α5, α9, β2 and β4 and the muscarinic M3 and M5 AChR subunits. Our results exclude a role of the cholinergic system in the initiation of keratinocyte proliferation in the basal epidermal layer but point towards a role of epidermal AChR in suprabasal processes, most likely terminal differentiation and barrier formation as has been shown in other systems. Most importantly, mast cells are targets of paracrine and endocrine effects mediated by ACh and choline thus modulating inflammatory processes like guttate psoriasis and explaining the clinical efficacity of anticholinergic drugs like atropine.