Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation

Immunity. 2019 Oct 15;51(4):682-695.e6. doi: 10.1016/j.immuni.2019.06.009. Epub 2019 Jul 25.


Innate lymphocytes maintain tissue homeostasis at mucosal barriers, with group 2 innate lymphoid cells (ILC2s) producing type 2 cytokines and controlling helminth infection. While the molecular understanding of ILC2 responses has advanced, the complexity of microenvironmental factors impacting ILC2s is becoming increasingly apparent. Herein, we used single-cell analysis to explore the diversity of gene expression among lung lymphocytes during helminth infection. Following infection, we identified a subset of ILC2s that preferentially expressed Il5-encoding interleukin (IL)-5, together with Calca-encoding calcitonin gene-related peptide (CGRP) and its cognate receptor components. CGRP in concert with IL-33 and neuromedin U (NMU) supported IL-5 but constrained IL-13 expression and ILC2 proliferation. Without CGRP signaling, ILC2 responses and worm expulsion were enhanced. Collectively, these data point to CGRP as a context-dependent negative regulatory factor that shapes innate lymphocyte responses to alarmins and neuropeptides during type 2 innate immune responses.

Keywords: CGRP; IL-33; NMU; Nippostrongylus brasiliensis; cytokines; host defense; immunoregulation; innate lymphoid cells; neuropeptides; single-cell RNA-seq.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / metabolism
  • Immunity, Innate
  • Inflammation / immunology*
  • Interleukin-33 / metabolism
  • Lymphocytes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuropeptides / metabolism
  • Nippostrongylus / physiology*
  • Receptors, Calcitonin Gene-Related Peptide / genetics
  • Receptors, Calcitonin Gene-Related Peptide / metabolism*
  • Single-Cell Analysis
  • Strongylida Infections / immunology*
  • Th2 Cells / immunology
  • Transplantation Chimera


  • Cytokines
  • Interleukin-33
  • Neuropeptides
  • Receptors, Calcitonin Gene-Related Peptide
  • neuromedin U