Protective role of G-CSF in dextran sulfate sodium-induced acute colitis through generating gut-homing macrophages |
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| Affiliation: | 1. Department of Microbiology and Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario N6G 2V4, Canada;2. Center for Human Immunology, University of Western Ontario, London, Ontario N6G 2V4, Canada;1. National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, Ministry of Health, WHO Collaborating Center for Malaria, Schistosomiasis and Filariasis, Shanghai, People’s Republic of China;2. Hunan Institute of Schistosomiasis Control, Yueyang, People’s Republic of China;1. Department of Hematology,;2. Department of Blood Transfusion and Transplantation Immunology, Fukushima, Japan;3. Department of Diagnostic Pathology, Fukushima, Japan;4. Department of Cardiovascular Medicine, Fukushima, Japan;5. Department of Pharmacology, Fukushima Medical University, Fukushima, Japan;;6. Department of Human Lifesciences, Fukushima Medical University School of Nursing, Fukushima, Japan;;7. Department of Hematology, The Children''s Hospital of Philadelphia, Philadelphia, PA;;8. Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan;;9. Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan;10. Department of Cellular and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan;1. Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8502, Japan;2. Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan |
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| Abstract: | Granulocyte colony-stimulating factor (G-CSF) is a pleiotropic cytokine best known for its role in promoting the generation and function of neutrophils. G-CSF is also found to be involved in macrophage generation and immune regulation; however, its in vivo role in immune homeostasis is largely unknown. Here, we examined the role of G-CSF in dextran sulfate sodium (DSS)-induced acute colitis using G-CSF receptor-deficient (G-CSFR−/−) mice. Mice were administered with 1.5% DSS in drinking water for 5 days, and the severity of colitis was measured for the next 5 days. GCSFR−/− mice were more susceptible to DSS-induced colitis than G-CSFR+/+ or G-CSFR−/+ mice. G-CSFR−/− mice harbored less F4/80+ macrophages, but a similar number of neutrophils, in the intestine. In vitro, bone marrow-derived macrophages prepared in the presence of both G-CSF and macrophage colony-stimulating factor (M-CSF) (G-BMDM) expressed higher levels of regulatory macrophage markers such as programmed death ligand 2 (PDL2), CD71 and CD206, but not in arginase I, transforming growth factor (TGF)-β, Ym1 (chitinase-like 3) and FIZZ1 (found in inflammatory zone 1), and lower levels of inducible nitric oxide synthase (iNOS), CD80 and CD86 than bone marrow-derived macrophages prepared in the presence of M-CSF alone (BMDM), in response to interleukin (IL)-4/IL-13 and lipopolysaccharide (LPS)/interferon (IFN)-γ, respectively. Adoptive transfer of G-BMDM, but not BMDM, protected G-CSFR−/− mice from DSS-induced colitis, and suppressed expression of tumor necrosis factor (TNF)-α, IL-1β and iNOS in the intestine. These results suggest that G-CSF plays an important role in preventing colitis, likely through populating immune regulatory macrophages in the intestine. |
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| Keywords: | G-CSF G-CSF receptor Colitis Macrophage |
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