Transcriptional Atlas of Intestinal Immune Cells Reveals that Neuropeptide α-CGRP Modulates Group 2 Innate Lymphoid Cell Responses

Immunity. 2019 Oct 15;51(4):696-708.e9. doi: 10.1016/j.immuni.2019.09.004.


Signaling abnormalities in immune responses in the small intestine can trigger chronic type 2 inflammation involving interaction of multiple immune cell types. To systematically characterize this response, we analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA sequencing (scRNA-seq) at steady state and after induction of a type 2 inflammatory reaction to ovalbumin (OVA). Computational analysis revealed broad shifts in both cell-type composition and cell programs in response to the inflammation, especially in group 2 innate lymphoid cells (ILC2s). Inflammation induced the expression of exon 5 of Calca, which encodes the alpha-calcitonin gene-related peptide (α-CGRP), in intestinal KLRG1+ ILC2s. α-CGRP antagonized KLRG1+ ILC2s proliferation but promoted IL-5 expression. Genetic perturbation of α-CGRP increased the proportion of intestinal KLRG1+ ILC2s. Our work highlights a model where α-CGRP-mediated neuronal signaling is critical for suppressing ILC2 expansion and maintaining homeostasis of the type 2 immune machinery.

Keywords: CGRP; allergic inflammation; batch effect correction; intestinal immune cell atlas; neuro-immune interaction; neuropeptides; scRNA-seq; single cell genomics; topic model; type 2 innate lymphoid cells.

Publication types

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

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / genetics
  • Calcitonin Gene-Related Peptide / metabolism*
  • Cells, Cultured
  • Computational Biology
  • Immunity, Innate
  • Inflammation / immunology*
  • Interleukin-5 / genetics
  • Interleukin-5 / metabolism
  • Intestines / immunology*
  • Lectins, C-Type / metabolism
  • Lymphocytes / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Receptors, Immunologic / metabolism
  • Sequence Analysis, RNA
  • Signal Transduction
  • Single-Cell Analysis
  • Th2 Cells / immunology
  • Transcriptome
  • Up-Regulation


  • Calca protein, mouse
  • Interleukin-5
  • Klrg1 protein, mouse
  • Lectins, C-Type
  • Neuropeptides
  • Receptors, Immunologic
  • Calcitonin Gene-Related Peptide