Inhibition of thymocyte autophagy-associated CD4+T thymopoiesis is involved in asthma susceptibility in mice exposed to caffeine prenatally

Arch Toxicol. 2019 May;93(5):1323-1335. doi: 10.1007/s00204-019-02418-5. Epub 2019 Feb 25.

Abstract

Our previous studies demonstrated that prenatal caffeine exposure (PCE) caused thymopoiesis inhibition, immune disorders, and airway remodeling in offspring, which raises the question of whether PCE is a risk factor for postnatal asthma. Meanwhile, the mechanism of PCE-induced thymopoiesis inhibition is not clear yet. Considering caffeine's pro-autophagy effects (lacking evidence in thymus) and the important role of autophagy in maintaining thymopoiesis, this study aimed to investigate whether PCE contributes to asthma susceptibility, and further explore the molecular mechanisms of thymopoiesis inhibition from the perspective of pro-autophagy effects of caffeine both in vivo and in vitro. The PCE mouse model was established by 96 mg/kg/day caffeine administration from gestational day (GD) 9-GD 18, and an asthma model was established on the offspring by ovalbumin sensitization and challenge. The results confirmed our hypothesis that PCE could suppress pulmonary CD4+T development and aggravate allergen-induced asthma symptoms in the offspring. In fetuses, PCE significantly suppressed A2AR-PKA signaling, upregulated Beclin1-LC3II autophagy, promoted Bcl10 degradation, reduced A20 expression, and inhibited CD4+T thymopoiesis. Similar results were also observed in 4 µM caffeine-treated thymocytes in vitro. Moreover, inhibiting A2AR by antagonist (SCH 58261) performed the same downstream biological effects as caffeine treatment, and autophagy inhibitor (BafilomycinA1) clearly abolished the caffeine-induced Bcl10 degradation and A20 suppression. In conclusion, our findings, for the first time, showed that PCE could attenuate CD4+T thymopoiesis and suppress pulmonary CD4+T development by directly enhancing autophagy in thymocytes, and provided a firm experimental evidence that PCE is a risk factor for postnatal asthma.

Keywords: Asthma; Autophagy; CD4+T deviation; Immunotoxicity; Prenatal caffeine exposure; Thymocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / etiology*
  • Autophagy / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Caffeine / administration & dosage
  • Caffeine / toxicity*
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / toxicity
  • Female
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Pregnancy
  • Prenatal Exposure Delayed Effects / physiopathology*
  • Thymocytes / cytology
  • Thymocytes / drug effects*

Substances

  • Central Nervous System Stimulants
  • Caffeine