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

Abstract

Summary 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.

Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial

“…In parallel, a reduction in GM‐CSF was observed. GM‐CSF is the main activator of the proinflammatory M1 macrophage phenotype; hence, its reduction could lead to macrophage polarization toward alternatively activated M2 macrophages 51 . The levels of PDGF‐BB also resulted significantly reduced in the UC‐MSC treatment group.…”

“…GM-CSF is the main activator of the proinflammatory M1 macrophage phenotype; hence, its reduction could lead to macrophage polarization toward alternatively activated M2 macrophages. 51 The levels of PDGF-BB also resulted significantly reduced in the UC-MSC treatment group. Notably, PDGF-BB stimulates mesenchymal cell activation, airway smooth muscle cell proliferation and migration, lung fibroblast cytokine production, and activation of nociceptive neurons.…”

ILC3, a Central Innate Immune Component of the Gut-Brain Axis in Multiple Sclerosis

“…Still, it has to be noted that several studies imply proinflammatory and disease-promoting activity of ILC3. For example, GM-CSF production by ILC3 was associated with enhanced maturation and polarization of inflammatory intestinal Mf and with the intestinal inflammatory response as observed in colitis (80,81). Also, MHC class II + ILC3 were shown to co-stimulate effector T cells in chronic colitis (59).…”

Immunometabolism of Tissue-Resident Macrophages – An Appraisal of the Current Knowledge and Cutting-Edge Methods and Technologies

“…For instance, alveolar macrophages rely on different metabolic programs depending on the type of infection (121,123). Additionally, emerging evidence suggests that commensal microbes contribute to metabolic reprogramming of intestinal TRM populations (124)(125)(126). Given that tissue-specific infectious defense is a core function of TRMs, moving beyond LPS will certainly provide new insights into unique TRM metabolic programs used during infectious immunity.…”