Asthma susceptibility in prenatal nicotine-exposed mice attributed to
β-catenin increase during CD4+ T cell development.
Background. Asthma, the most frequent allergic airway disease, is
related to maternal exposure to cigarette smoke. Our previous studies
demonstrated that prenatal exposure to nicotine (PNE), the major active
product of smoking, impairs fetal thymopoiesis and CD4+ T cell
development after birth. This study aimed to investigate whether PNE
contributes to asthma susceptibility through CD4+ T cell development
alterations. Methods. A PNE model was established by administering 3
mg/kg/day nicotine to maternal mice, and then an ovalbumin-induced
asthma model was established in the offspring. β-Catenin and downstream
pathways were further inhibited in vitro to confirm the molecular
mechanisms underlying the phenotype observed during the in vivo phase.
Results. PNE induced Th2 and Th17 biases at developmental checkpoints
and aggravated asthma symptoms in the offspring. In fetuses, PNE
up-regulated α7 nAChR, activated PI3K-AKT, promoted β-catenin level
increase, and established potential Th2- and Th17-biased gene expression
patterns during thymopoiesis, which persisted after birth. Similar
results were also observed in 1 μM nicotine-treated thymocytes in vitro.
Moreover, inhibiting PI3K-AKT by LY294002 abrogated nicotine-mediated
β-catenin level increase and thymopoiesis abnormalities, and an α7 nAChR
antagonist (α-btx) also reversed nicotine-induced PI3K-AKT activation.
Conclusion. Our findings provide strong evidence that PNE is a risk
factor for T cell deviation and postnatal asthma, and revealed that
nicotine-induced β-catenin level increase induces thymopoiesis