GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation
Tomas Castro‐Dopico, Aaron Fleming, Thomas W. Dennison, John R. Ferdinand, Katherine Harcourt, Benjamin J. Stewart, M. Zaeem Cader, Zewen Kelvin Tuong, Chenzhi Jing, Laurence S. C. Lok, Rebeccah J. Mathews, Anaïs Portet, Arthur Kaser, Simon Clare, Menna R. Clatworthy
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.