GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation.

Abstract

Macrophages play a central role in intestinal immunity, but inappropriate macrophage activation is associated with inflammatory bowel disease (IBD). Here, we identify granulocyte-macrophage colony stimulating factor (GM-CSF) as a critical regulator of intestinal macrophage activation in patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis. We find that GM-CSF drives the maturation and polarization of inflammatory intestinal macrophages, promoting anti-microbial functions while suppressing wound-healing transcriptional programs. Group 3 innate lymphoid cells (ILC3s) are a major source of GM-CSF in intestinal inflammation, with a strong positive correlation observed between ILC or CSF2 transcripts and M1 macrophage signatures in IBD mucosal biopsies. Furthermore, GM-CSF-dependent macrophage polarization results in a positive feedback loop that augmented ILC3 activation and type 17 immunity. Together, our data reveal an important role for GM-CSF-mediated ILC-macrophage crosstalk in calibrating intestinal macrophage phenotype to enhance anti-bacterial responses, while inhibiting pro-repair functions associated with fibrosis and stricturing, with important clinical implications.

• Authors: Tomas Castro-Dopico, Aaron Fleming, Thomas W Dennison, John R Ferdinand, Katherine Harcourt, Benjamin J Stewart, Zaeem Cader, Zewen K Tuong, Chenzhi Jing, Laurence S C Lok, Rebeccah J Mathews, Anaïs Portet, Arthur Kaser, Simon Clare, Menna R Clatworthy
• Journal: Cell reports (Cell Rep) Vol. 32 Issue 1 Pg. 107857 (07 07 2020) ISSN: 2211-1247 [Electronic] United States
• PMID: 32640223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Cell Polarity
• Citrobacter rodentium (physiology)
• Colitis (complications, immunology, pathology)
• Enterobacteriaceae Infections (pathology)
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Humans
• Immunity, Innate
• Inflammation (pathology)
• Intestines (pathology)
• Lymphocytes (immunology)
• Macrophage Activation
• Macrophages (pathology)
• Mice, Inbred C57BL
• Phenotype
• Wound Healing