Granulocyte-macrophage colony-stimulating factor elicits bone marrow-derived cells that promote efficient colonic mucosal healing.
BACKGROUND
Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy is effective in treating some Crohn's disease (CD) patients and protects mice from colitis induced by dextran sulfate sodium (DSS) administration. However, its mechanisms of action remain elusive. We hypothesized that GM-CSF affects intestinal mucosal repair.


METHODS
DSS colitic mice were treated with daily pegylated GM-CSF or saline and clinical, histological, and inflammatory parameters were kinetically evaluated. Further, the role of bone marrow-derived cells in the impact of GM-CSF therapy on DSS colitis was addressed using cell transfers.


RESULTS
GM-CSF therapy reduced clinical signs of colitis and the release of inflammatory mediators. GM-CSF therapy improved mucosal repair, with faster ulcer reepithelialization, accelerated hyperproliferative response of epithelial cells in ulcer-adjacent crypts, and lower colonoscopic ulceration scores in GM-CSF-administered mice relative to untreated mice. We observed that GM-CSF-induced promotion of mucosal repair is timely associated with a reduction in neutrophil numbers and increased accumulation of CD11b(+) monocytic cells in colon tissues. Importantly, transfer of splenic GM-CSF-induced CD11b(+) myeloid cells into DSS-exposed mice improved colitis, and lethally irradiated GM-CSF receptor-deficient mice reconstituted with wildtype bone marrow cells were protected from DSS-induced colitis upon GM-CSF therapy. Lastly, GM-CSF-induced CD11b(+) myeloid cells were shown to promote in vitro wound repair.


CONCLUSIONS
Our study shows that GM-CSF-dependent stimulation of bone marrow-derived cells during DSS-induced colitis accelerates colonic tissue repair. These data provide a putative mechanism for the observed beneficial effects of GM-CSF therapy in Crohn's disease.
Bernasconi
Eric
E
Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.
Favre
Laurent
L
Maillard
Michel H
MH
Bachmann
Daniel
D
Pythoud
Catherine
C
Bouzourene
Hanifa
H
Croze
Ed
E
Velichko
Sharlene
S
Parkinson
John
J
Michetti
Pierre
P
Velin
Dominique
D
D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D003106:Colon / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D003424:Crohn Disease / Q000188:drug therapy / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000187:drug effects / Q000473:pathology; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016264:Dextran Sulfate