Age-Related Dopaminergic Innervation Augments T Helper 2-Type Allergic Inflammation in the Postnatal Lung

Immunity. 2019 Dec 17;51(6):1102-1118.e7. doi: 10.1016/j.immuni.2019.10.002. Epub 2019 Nov 19.


Young children are more susceptible to developing allergic asthma than adults. As neural innervation of the peripheral tissue continues to develop after birth, neurons may modulate tissue inflammation in an age-related manner. Here we showed that sympathetic nerves underwent a dopaminergic-to-adrenergic transition during post-natal development of the lung in mice and humans. Dopamine signaled through a specific dopamine receptor (DRD4) to promote T helper 2 (Th2) cell differentiation. The dopamine-DRD4 pathway acted synergistically with the cytokine IL-4 by upregulating IL-2-STAT5 signaling and reducing inhibitory histone trimethylation at Th2 gene loci. In murine models of allergen exposure, the dopamine-DRD4 pathway augmented Th2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. Taken together, the communication between dopaminergic nerves and CD4+ T cells provides an age-related mechanism underlying the susceptibility to allergic inflammation in the early lung.

Keywords: DRD4; IL-2; IL-4; Th2; adrenergic innervation; allergic asthma; childhood asthma; dopamine; lung; sympathetic nerve.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adrenergic Neurons / cytology*
  • Adult
  • Age Factors
  • Aged
  • Animals
  • Asthma / immunology
  • Asthma / pathology*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Dopamine / metabolism*
  • Dopaminergic Neurons / cytology*
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Interleukin-2 / metabolism
  • Interleukin-4 / immunology
  • Lung / immunology
  • Lung / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Neurogenesis / physiology
  • Receptors, Dopamine D4 / metabolism
  • STAT5 Transcription Factor / metabolism
  • Sympathetic Nervous System / cytology
  • Th2 Cells / immunology*


  • Drd4 protein, mouse
  • Il4 protein, mouse
  • Interleukin-2
  • STAT5 Transcription Factor
  • Stat5a protein, mouse
  • Receptors, Dopamine D4
  • Interleukin-4
  • Dopamine