title: Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs.
abstract: In 1929, Dale and Dudley described the first reported natural occurrence of acetylcholine (ACh) in an animal's body. They identified this ACh in the spleens of horses and oxen, which we now know suggests possible involvement of ACh in the regulation of lymphocyte activity and immune function. However, the source and function of splenic ACh were left unexplored for several decades. Recent studies on the source of ACh in the blood revealed ACh synthesis catalyzed by choline acetyltransferase (ChAT) in CD4(+) T cells. T and B cells, macrophages and dendritic cells (DCs) all express all five muscarinic ACh receptor subtypes (mAChRs) and several subtypes of nicotinic AChRs (nAChRs), including α7 nAChRs. Stimulation of these mAChRs and nAChRs by their respective agonists causes functional and biochemical changes in the cells. Using AChR knockout mice, we found that M(1)/M(5) mAChR signaling up-regulates IgG(1) and pro-inflammatory cytokine production, while α7 nAChR signaling has the opposite effect. These findings suggest that ACh synthesized by T cells acts in an autocrine/paracrine fashion at AChRs on various immune cells to modulate immune function. In addition, an endogenous allosteric and/or orthosteric α7 nAChR ligand, SLURP-1, facilitates functional development of T cells and increases ACh synthesis via up-regulation of ChAT mRNA expression. SLURP-1 is expressed in CD205(+) DCs residing in the tonsil in close proximity to T cells, macrophages and B cells. Collectively, these findings suggest that ACh released from T cells along with SLURP-1 regulates cytokine production by activating α7 nAChRs on various immune cells, thereby facilitating T cell development and/or differentiation, leading to immune modulation.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan. Electronic address: koichiro-jk@piano.ocn.ne.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kawashima
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Moriwaki
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Misawa
authors.affiliation: Department of Anatomy, University of Fukui Faculty of Medical Sciences, Matsuoka, Fukui 910-1193, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Horiguchi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D013045:Species Specificity; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D064569:alpha7 Nicotinic Acetylcholine Receptor; D000109:Acetylcholine
keywords: Acetylcholine (ACh); Choline acetyltransferase (ChAT); Cytokine; Nicotinic ACh receptor (nAChR); SLURP; Spleen