Nicotinic Receptor Alpha7 Expression Identifies a Novel Hematopoietic Progenitor Lineage

How inflammatory responses are mechanistically modulated by nicotinic acetylcholine receptors (nAChR), especially by receptors composed of alpha7 (alpha 7) subunits, is poorly defined. This includes a precise definition of cells that express alpha 7 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 alpha 7 gene that when crossed with a reporter mouse expressing Rosa26-LoxP (yellow fluorescent protein (YFP)) marks in the offspring those cells of the alpha 7 cell lineage (alpha 7(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 alpha 7(lin+), although variability between litter mates in this value is observed. This hematopoietic alpha 7(lin+) subpopulation is also found in Sca1(+)cKit(+) BM cells suggesting the alpha 7 lineage is established early during hematopoiesis and the ratio remains stable in the individual thereafter as measured for at least 18 months. Both alpha 7(lin+) and alpha 7(lin-) BM cells can reconstitute the immune system of naive irradiated recipient mice and the alpha 7(lin+):alpha 7(lin-) beginning ratio is stable in the recipient after reconstitution. Functionally the alpha 7(lin+):alpha 7(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 alpha 7(lin+) cells. These studies demonstrate that alpha 7(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 alpha 7 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.