RESUMO
Microglia migrate to the cerebral cortex during early embryonic stages. However, the precise mechanisms underlying microglia migration remain incompletely understood. As an extracellular matrix protein, Netrin-1 is involved in modulating the motility of diverse cells. In this paper, we found that Netrin-1 promoted microglial BV2 cell migration in vitro. Mechanism studies indicated that the activation of GSK3ß activity contributed to Netrin-1-mediated microglia migration. Furthermore, Integrin α6/ß1 might be the relevant receptor. Single-cell data analysis revealed the higher expression of Integrin α6 subunit and ß1 subunit in microglia in comparison with classical receptors, including Dcc, Neo1, Unc5a, Unc5b, Unc5c, Unc5d, and Dscam. Microscale thermophoresis (MST) measurement confirmed the high binding affinity between Integrin α6/ß1 and Netrin-1. Importantly, activation of Integrin α6/ß1 with IKVAV peptides mirrored the microglia migration and GSK3 activation induced by Netrin-1. Finally, conditional knockout (CKO) of Netrin-1 in radial glial cells and their progeny led to a reduction in microglia population in the cerebral cortex at early developmental stages. Together, our findings highlight the role of Netrin-1 in microglia migration and underscore its therapeutic potential in microglia-related brain diseases.
Assuntos
Movimento Celular , Microglia , Netrina-1 , Netrina-1/metabolismo , Netrina-1/genética , Microglia/metabolismo , Animais , Camundongos , Camundongos Knockout , Córtex Cerebral/metabolismo , Córtex Cerebral/citologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Linhagem Celular , Integrina beta1/metabolismo , Integrina beta1/genéticaRESUMO
In order to explore the pollution characteristics and health risks of heavy metals in dust from roads around non-ferrous smelting activities in different regions, dust samples from urban roads, non-ferrous smelting industry park roads, and tunnel roads were collected from the Mengzi area of Yunnan Province. The dust samples were suspended on Teflon filters by re-suspension equipment to obtain PM2.5 and PM10 samples. Eight heavy metals (Cr, Mn, Ni, Cu, Zn, As, Cd, and Pb) were analyzed by ICP-MS. The results showed that the average content of the total heavy metals in PM2.5 was higher than that in PM10. The average contents of Pb, Cd, As, and Zn were highest in all three types of road dust, and the difference in the total average content in different types of road dust was ranked as:tunnel roads > non-ferrous smelting industrial park roads > urban roads. The average contents of Pb and As in PM2.5 from the tunnel road dust were higher than other heavy metals, and reached up to 92338.3 mg·kg-1 and 12457.7 mg·kg-1, respectively. The average contents of Pb and Zn in PM2.5 from the industrial park road dust were the highest of all heavy metals (4381.7 mg·kg-1 and 4685.0 mg·kg-1, respectively). The average content of Zn and Pb in PM2.5 were the highest of all the heavy metals in the urban road dust (1952.6 mg·kg-1 and 1944.8 mg·kg-1, respectively). The average contents of Cu, Zn, As, Cd, and Pb in the different types of road dust were all higher than their background values in Yunnan Province. The results of the enrichment factor analysis and principal component analysis indicated that Cu, Zn, As, Cd, and Pb were obviously enriched in all three types of road dust, which were significantly affected by the non-ferrous smelting industry and traffic sources. In contrast, Cr, Mn, and Ni were not obviously enriched in the three types of road dust and were less affected by anthropogenic sources. The results of the health risk assessment testified that ingestion was the main exposure route, and that the children's non-carcinogenic risk was higher than that of adults. In PM2.5, As, Cd, and Pb in all types of road dust were associated with non-carcinogenic risks for adults and children. In PM10, As, Cd, and Pb in dust from the non-ferrous smelting industry park roads and tunnel roads had non-carcinogenic risks for humans. As in PM10 from the urban road dust was associated with a non-carcinogenic risk for children, whereas As in dust from the tunnel roads had carcinogenic risks.