Augmented autophagy suppresses thymocytes development via Bcl10/p-p65 pathway in prenatal nicotine exposed fetal mice.
Tobacco smoke is a common global environmental pollutant. Maternal tobacco smoke/nicotine exposure has long-term toxic effects on immune organs. We previously found that prenatal nicotine exposure (PNE)-induced programmed immune diseases caused by fetal thymic hypoplasia, but the mechanism still unknown. Autophagy has important functions in maintaining thymopoiesis, whether autophagy was involved in PNE-inhibited fetal thymocytes development is also obscure. Therefore, this study aimed to investigate how nicotine changed the development of fetal thymocytes from the perspective of autophagy in vivo and in vitro. PNE model was established by 3 mg/kg nicotine administration in Balb/c mice from gestational day 9 to 18. The results showed that PNE reduced the percentage and absolute number of CD69-CD4+SP cells, suggesting a block of fetal thymocytes mature. PNE promoted autophagosome formation, autophagy related proteins (Beclin1, LC3I/II) expression, and upregulated α7 nAChR as well as AMPK phosphorylation in fetal thymus. Moreover, PNE promoted Bcl10 degradation via autophagy-mediated proteolysis and inhibited p65 activation, blocking the transition of thymocytes between the DP to SP stage. Further, primary thymocytes were treated with nicotine in vitro and showed induced autophagy in a dose- and time-dependent manner. In addition, nicotine-inhibited CD69-CD4+SP cells and the Bcl10/p-p65 pathway have been reversed by an autophagy inhibitor. The α7 nAChR specific antagonist abrogated nicotine-induced AMPK phosphorylation and autophagy initiation. In conclusion, our findings showed that PNE repressed the Bcl10/p-p65 development pathway of CD4+SP cells by triggering autophagy, and illuminated the developmental origin mechanism of programmed immune diseases in PNE offspring.
['Yan|Hui-Yi|HY|', 'Wen|Xiao|X|', 'Chen|Lan-Zhou|LZ|', 'Feng|Yi-Ting|YT|', 'Liu|Han-Xiao|HX|', 'Qu|Wen|W|', 'Zhao|Wen-Hao|WH|', 'Xu|Dong-Qin|DQ|', 'Ping|Jie|J|']
D000818:Animals D001343:Autophagy D000074018:B-Cell CLL-Lymphoma 10 Protein D000071186:Beclin-1 D005260:Female D005333:Fetus D015386:Hazardous Substances D008213:Lymphocyte Activation D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D009538:Nicotine D011247:Pregnancy D011297:Prenatal Exposure Delayed Effects D060168:Thymocytes D014815:Vitamins
Autophagy Thymocytes Prenatal nicotine exposure α7 nAchR CD4(+)SP