GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation.
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Castro-Dopico, T., Fleming, A., Dennison, T., Ferdinand, J., Harcourt, K., Stewart, B. J., Cader, Z., et al. (2020). GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation.. Cell reports, 32 (1), 107857. https://doi.org/10.1016/j.celrep.2020.107857
Macrophages play a central role in intestinal immunity, but inappropriate macrophage activation is associated with inflammatory bowel disease (IBD). Here, we identify GM-CSF as a critical regulator of intestinal macrophage activation in patients with IBD and mice with dextran sodium sulphate (DSS)-induced colitis. We find that GM-CSF drives the maturation and polarisation of inflammatory intestinal macrophages, promoting anti-microbial functions while suppressing wound-healing transcriptional programmes. 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 polarisation 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, whilst inhibiting pro-repair functions associated with fibrosis and stricturing, with important clinical implications.
Intestines, Lymphocytes, Macrophages, Animals, Mice, Inbred C57BL, Humans, Citrobacter rodentium, Enterobacteriaceae Infections, Colitis, Inflammation, Granulocyte-Macrophage Colony-Stimulating Factor, Wound Healing, Cell Polarity, Macrophage Activation, Phenotype, Immunity, Innate
Arthritis Research UK (21777)
Wellcome Trust (102163/B/13/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
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External DOI: https://doi.org/10.1016/j.celrep.2020.107857
This record's URL: https://www.repository.cam.ac.uk/handle/1810/306875
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