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.

Osteal Tissue Macrophages Are Intercalated throughout Human and Mouse Bone Lining Tissues and Regulate Osteoblast Function In Vitro and In Vivo

“…For example, resident and recruited macrophages have been shown to control survival, degeneration, and replacement of olfactory sensory neurons, another system in which turnover is highly regulated (59). Our data show that OsteoMacs, like macrophages in many other organs (4), occupy a precise anatomical niche and that they are integral to maintenance of osteal tissue homeostasis.…”

Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies

“…This method proved a breakthrough in the study of macrophages, but also showed that, depending on the condition, the effect of the macrophage elimination could be beneficial as well as detrimental. [30][31][32][33][34] The current perception that macrophages are composed of functionally distinct sub-populations, termed M1 and M2, now explains these differential effects and emphasizes the importance of selectively targeting these different sub-populations. During chronic inflammation, there is strong evidence for an inappropriate persistence of M1 macrophages, which are directly associated with the development and perpetuation of many chronic inflammatory and autoimmune diseases.…”

Macrophage-mediated neuroprotection and neurogenesis in the olfactory epithelium

“…We demonstrated that combined intranasal and intravenous administration of Lip-C induced a significant 38 and 35% reduction in resident and recruited macrophages in the OE of sham and 48 h OBX mice, respectively (6). Macrophage depletion in the OE resulted in a decrease in OE thickness and the numbers of olfactory marker protein (OMP) ϩ mOSNs and 5-bromo-2-deoxyuridine (BrdU) ϩ proliferating basal cells in sham and 48 h OBX mice.…”

“…More specifically, recent studies (6,23,33) on the interaction between the immune system and neurogenesis in the OE have strengthened the case for the participation of macrophages in the regulation of OSN survival and the proliferation, differentiation, and maturation of OSN basal progenitor cells in the unperturbed OE and during OE remodeling as a result of olfactory bulbectomy (OBX)-induced OSN apoptosis.…”

“…We previously introduced the use of liposome-encapsulated clodronate (Lip-C), which induces apoptosis selectively in macrophages, to deplete resident and recruited macrophages in the OE (6). Analogous to OBX, where mOSNs are selectively depleted through induced retrograde apoptosis, intranasal administration of Lip-C selectively depletes macrophages in the nasal mucosa.…”