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

Heping Xu; Jiarui Ding; Caroline B M Porter; Antonia Wallrapp; Marcin Tabaka; Sai Ma; Shujie Fu; Xuanxuan Guo; Samantha J Riesenfeld; Chienwen Su; Danielle Dionne; Lan T Nguyen; Ariel Lefkovith; Orr Ashenberg; Patrick R Burkett; Hai Ning Shi; Orit Rozenblatt-Rosen; Daniel B Graham; Vijay K Kuchroo; Aviv Regev; Ramnik J Xavier

doi:10.1016/j.immuni.2019.09.004

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.

Authors

Heping Xu¹, Jiarui Ding², Caroline B M Porter², Antonia Wallrapp³, Marcin Tabaka², Sai Ma², Shujie Fu⁴, Xuanxuan Guo⁴, Samantha J Riesenfeld², Chienwen Su⁵, Danielle Dionne², Lan T Nguyen², Ariel Lefkovith², Orr Ashenberg², Patrick R Burkett³, Hai Ning Shi⁵, Orit Rozenblatt-Rosen², Daniel B Graham⁶, Vijay K Kuchroo⁷, Aviv Regev⁸, Ramnik J Xavier⁹

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China; Laboratory of Systems Immunology, Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang Province, China. Electronic address: xuheping@westlake.edu.cn.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02114, USA.
⁴ Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China; Laboratory of Systems Immunology, Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang Province, China.
⁵ Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02114, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02114, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: aregev@broadinstitute.org.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

Abstract

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding