B cell-derived acetylcholine mitigates skin inflammation in mice through α9 nicotinic acetylcholine receptor-mediated signaling

• 成果类型: Article
• 署名作者: Foffi, Erica; Rugolo, Francesco; Ramamurthy, Nisha; Haight, Jillian; Helke, Simone; You-Ten, Annick; Tobin, Chantal; Jafari, Soode Moghadas; Elia, Andrew J.; Berger, Thorsten; Candi, Eleonora; Melino, Gerry; Mak, Tak W.
• 署名单位: University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; IRCCS Istituto Dermopatico dell'Immacolata (IDI); University of Rome Tor Vergata; University of Hong Kong; University of Toronto; University of Toronto
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11739
• DOI: 10.1073/pnas.2501960122
• 发表日期: 2025-04-29
• 关键词: cholinergic system; t-cells; psoriasis; initiation

摘要

Chronic inflammatory skin disorders are characterized by keratinocyte hyperproliferation and hyperactivation as well as immune cell infiltration. We investigated whether immune cell-derived acetylcholine (ACh) is a modulator of skin inflammation in mice. Here, we identify skin epithelial B cells as a key source of ACh that damps down inflammation. We used imiquimod (IMQ) to induce inflammatory skin disease (ISD) in mice lacking ACh production specifically in B cells (ChATfl/fl;Mb1-Cre mice). Increased keratinocyte proliferation, epidermal thickening, and elevated levels of proinflammatory cytokines resulted. ACh binding to alpha 9 nicotinic ACh receptor (encoded by Chrna9) expressed on wild-type mouse keratinocytes reduced their proliferation. Chrna9-deficient mice exhibited the same exacerbated ISD phenotype as ChATfl/fl;Mb1-Cre mice following IMQ induction. Our data suggest that B cell-derived ACh maintains skin homeostasis by modulating keratinocyte turnover and controlling immune-related inflammation. Therapeutic manipulation of this cholinergic pathway might mitigate both keratinocyte dysfunction and immune dysregulation in human patients, potentially pointing to treatments for ISDs such as psoriasis and related disorders.