Inhibition of Allergen-Induced Basophil Activation by ASM-024, a Nicotinic Receptor Ligand

Abstract

Background: Nicotinic acetylcholine receptors (nAChRs) were identified on eosinophils and shown to regulate inflammatory responses, but nAChR expression on basophils has not been explored yet. Objective: We investigated surface receptor expression of nAChR α₄, α₇ and α₁/α₃/α₅ subunits on basophils. Furthermore, we examined the effects of ASM-024, a synthetic nicotinic ligand, on in vitro anti-IgE and in vivo allergen-induced basophil activation. Methods: Basophils were enriched from the peripheral blood of allergic donors and the expression of nAChR subunits and muscarinic receptors was determined. Purified basophils were stimulated with anti-IgE in the presence of ASM-024 with or without muscarinic or nicotinic antagonists for the measurement of CD203c expression and histamine release. The effect of 9 days of treatment with 50 and 200 mg ASM-024 on basophil CD203c expression was examined in the blood of mild allergic asthmatics before and after allergen inhalation challenge. Results: nAChR α₄, α₇ and α₁/α₃/α₅ receptor subunit expression was detected on basophils. Stimulation of basophils with anti-IgE increased CD203c expression and histamine release, which was inhibited by ASM-024 (10^-5 to 10^-³ <smlcap>M</smlcap>, p < 0.05). The effect of ASM-024 was reversed in the presence of muscarinic and nicotinic antagonists. In subjects with mild asthma, ASM-024 inhalation significantly inhibited basophil CD203c expression measured 24 h after allergen challenge (p = 0.03). Conclusion: This study shows that ASM-024 inhibits IgE- and allergen-induced basophil activation through both nicotinic and muscarinic receptors, and suggests that ASM-024 may be an efficacious agent for modulating allergic asthma responses.

Granulocytes as models for human protein marker identification following nicotine exposure

“…; Watson et al . ). To isolate both basophils and eosinophils, cell populations can be selected for being CD45 and FcεR1‐positive cells (basophils), and for being CD45‐positive, CD16‐negative cells (eosinophils) (Watson et al .…”

“…Immunoreactivity was demonstrated using an antibody reactive with α1, α3, and α5, though more work is required to learn which of the three subunits are expressed in human basophils (Watson et al . ). Expression of α3, α4 and α7 subunit transcripts and protein in human eosinophils has been reported using a combination of RT‐PCR, ELISA, and immunohistochemistry (Blanchet et al .…”

“…Dimethylphenylpiperazinium and di‐ethyl‐phenylhomopiperazinium are two experimental cholinergic agonists with anti‐inflammatory properties (Watson et al . ). Activation of nAChRs following dimethylphenylpiperazinium exposure decreases MMP‐9 protein expression in eosinophils stimulated with 5‐oxo‐eicosatetraenoic acid.…”

“…This nicotinic antagonist‐sensitive decrease suggests that a decrease in allergen‐induced basophil activation is due in part due to nAChR activation (Watson et al . ). In summary, despite the currently limited information about protein changes in human basophils and eosinophils in response to nicotine exposure, protein markers do change when other nicotinic agonists stimulate nAChRs in human basophils and eosinophils.…”

News in Cellular Allergology: A Review of the Human Mast Cell and Basophil Granulocyte Literature from January 2013 to May 2015

“…Ingestion of the common dietary isoform of vitamin E, γ- tocopherol, significantly decreased the CD63 and CD203c reactivity of basophils ex vivo of mite-allergic patients [53]. The ingestion of ligands of nicotinic acetylcholine receptors on basophils inhibited FcεRI-mediated upregulation of CD203c [54]. …”