title: Nicotinic receptor alpha7 expression identifies a novel hematopoietic progenitor lineage.
abstract: How inflammatory responses are mechanistically modulated by nicotinic acetylcholine receptors (nAChR), especially by receptors composed of alpha7 (α7) subunits, is poorly defined. This includes a precise definition of cells that express α7 and how these impact on innate inflammatory responses. To this aim we used mice generated through homologous recombination that express an Ires-Cre-recombinase bi-cistronic extension of the endogenous α7 gene that when crossed with a reporter mouse expressing Rosa26-LoxP (yellow fluorescent protein (YFP)) marks in the offspring those cells of the α7 cell lineage (α7(lin+)). In the adult, on average 20-25 percent of the total CD45(+) myeloid and lymphoid cells of the bone marrow (BM), blood, spleen, lymph nodes, and Peyers patches are α7(lin+), although variability between litter mates in this value is observed. This hematopoietic α7(lin+) subpopulation is also found in Sca1(+)cKit(+) BM cells suggesting the α7 lineage is established early during hematopoiesis and the ratio remains stable in the individual thereafter as measured for at least 18 months. Both α7(lin+) and α7(lin-) BM cells can reconstitute the immune system of naïve irradiated recipient mice and the α7(lin+):α7(lin-) beginning ratio is stable in the recipient after reconstitution. Functionally the α7(lin+):α7(lin-) lineages differ in response to LPS challenge. Most notable is the response to LPS as demonstrated by an enhanced production of IL-12/23(p40) by the α7(lin+) cells. These studies demonstrate that α7(lin+) identifies a novel subpopulation of bone marrow cells that include hematopoietic progenitor cells that can re-populate an animal's inflammatory/immune system. These findings suggest that α7 exhibits a pleiotropic role in the hematopoietic system that includes both the direct modulation of pro-inflammatory cell composition and later in the adult the role of modulating pro-inflammatory responses that would impact upon an individual's lifelong response to inflammation and infection.
authors.affiliation: Geriatric Research, Education, and Clinical Center, Salt Lake City Veterans Administration Medical Center, Salt Lake City, Utah, United States of America. Lorise.Gahring@hsc.utah.edu
authors.forename: Lorise C
authors.initials: LC
authors.lastname: Gahring
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Enioutina
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Myers
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Spangrude
authors.forename: Olga V
authors.initials: OV
authors.lastname: Efimova
authors.forename: Todd W
authors.initials: TW
authors.lastname: Kelley
authors.forename: Petr
authors.initials: P
authors.lastname: Tvrdik
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.forename: Scott W
authors.initials: SW
authors.lastname: Rogers
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage / Q000187:drug effects / Q000276:immunology; D003433:Crosses, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000276:immunology*; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D053759:Interleukin-23 / Q000096:biosynthesis / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000276:immunology*; D014916:Whole-Body Irradiation; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D015415:Biomarkers; C579166:Chrna7 protein, mouse; D053759:Interleukin-23; D008070:Lipopolysaccharides; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D018664:Interleukin-12; D017493:Leukocyte Common Antigens