B cell–derived acetylcholine mitigates skin inflammation in mice through α9 nicotinic acetylcholine receptor–mediated signaling
Erica Foffi, Francesco Rugolo, Nisha Ramamurthy, Jillian Haight, Simone Helke, Annick You-Ten, Chantal Tobin, Soode Moghadas Jafari, Andrew Elia, Thorsten Berger, Eleonora Candi, Gerry Melino, Tak W. Mak
Abstract
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 (ChAT fl/fl;Mb1-Cre mice). Increased keratinocyte proliferation, epidermal thickening, and elevated levels of proinflammatory cytokines resulted. ACh binding to α9 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 ChAT fl/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.