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

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Castro-Dopico, Tomas 
Fleming, Aaron 
Dennison, Thomas W 
Ferdinand, John R 
Harcourt, Katherine 

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.

GM-CSF, anti-microbial defense, crosstalk, inflammatory bowel disease, innate lymphoid cells, macrophages, wound healing, Animals, Cell Polarity, Citrobacter rodentium, Colitis, Enterobacteriaceae Infections, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Immunity, Innate, Inflammation, Intestines, Lymphocytes, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Phenotype, Wound Healing
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Elsevier BV
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Medical Research Council (MR/N024907/1)
Arthritis Research UK (21777)
Wellcome Trust (102163/B/13/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)