Calcitonin Gene-Related Peptide Negatively Regulates Alarmin-Driven Type 2 Innate Lymphoid Cell Responses

Immunity. 2019 Oct 15;51(4):709-723.e6. doi: 10.1016/j.immuni.2019.09.005. Epub 2019 Oct 8.


Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production as well as exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.

Keywords: CGRP; Ramp1; airway inflammation; allergic inflammation; neuro-immune interaction; neuropeptides; type 2 innate lymphoid cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alarmins / metabolism
  • Animals
  • Calcitonin Gene-Related Peptide / genetics
  • Calcitonin Gene-Related Peptide / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Feedback, Physiological
  • Immunity, Innate
  • Interleukin-33 / metabolism
  • Lymphocytes / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuroimmunomodulation
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Receptors, Calcitonin Gene-Related Peptide / genetics
  • Receptors, Calcitonin Gene-Related Peptide / metabolism*
  • Signal Transduction
  • Th2 Cells / immunology


  • Alarmins
  • Interleukin-33
  • Neuropeptides
  • Receptors, Calcitonin Gene-Related Peptide
  • Calcitonin Gene-Related Peptide