title: Macrophage depletion in the murine olfactory epithelium leads to increased neuronal death and decreased neurogenesis.
abstract: Apoptosis of olfactory sensory neurons (OSNs) induced by olfactory bulbectomy (OBX) leads to the activation of resident macrophages within the olfactory epithelium (OE). These macrophages phagocytose degenerating OSNs and secrete chemokines, which recruit additional macrophages into the OE, and cytokines/growth factors, which regulate basal cell proliferation and differentiation and maturation of OSNs. In this study we apply for the first time the use of liposome-encapsulated clodronate to selectively deplete macrophages during the OSN degeneration/regeneration cycle in order to elucidate the role(s) of macrophages in regulating cellular mechanisms that lead to apoptosis and neurogenesis. Mice were injected intranasally and intravenously with either liposome-encapsulated clodronate or empty liposomes prior to and after OBX or sham OBX. At 48 hours after surgery the numbers of macrophages in the OE of both sham and OBX clodronate-treated mice were significantly reduced compared to liposome-treated controls (38% and 35%, respectively, P < 0.05). The reduction in macrophage numbers was accompanied by significant decreases in OE thickness (22% and 21%, P < 0.05), the number of mOSNs (1.2- and 1.9-fold, P < 0.05), and basal cell proliferation (7.6- and 3.8-fold, P < 0.005) in sham and OBX mice, respectively, compared to liposome-treated controls. In OBX mice there was also increased immunoreactivity for active caspase-3 in the OE and olfactory nerves of clodronate-treated OBX mice compared to liposome-treated controls. These results indicate that macrophages modulate the OSN population in the normal and target-ablated murine OE by influencing neuronal survival and basal cell proliferation, resulting in neurogenesis and replacement of mature OSNs.
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA. abord2@uky.edu
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Borders
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Getchell
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Etscheidt
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Donald A
authors.initials: DA
authors.lastname: Cohen
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Getchell
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000502:physiology*; D004002:Clodronic Acid / Q000494:pharmacology; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009830:Olfactory Bulb / Q000166:cytology / Q000293:injuries; D051842:Olfactory Marker Protein / Q000378:metabolism; D009831:Olfactory Mucosa / Q000166:cytology*; D038081:Organogenesis / Q000502:physiology*; D013997:Time Factors; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001973:Bromodeoxyuridine; D053148:Caspase 3; D004002:Clodronic Acid; D051842:Olfactory Marker Protein; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C497598:Omp protein, mouse