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Protective role of macrophage-derived ceruloplasmin in inflammatory bowel disease
Bakytzhan Bakhautdin1, Maria Febbraio, Esen Goksoy
1Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Objective:
Intestinal microflora and inflammatory cell infiltrates play critical roles in the pathogenesis of acute colitis. Ceruloplasmin is an acute-phase plasma protein produced by hepatocytes and activated macrophages, and has ferroxidase with bactericidal activities. The goal is to understand the role of ceruloplasmin in colitis progression in a genetically modified murine model.
Design:
Experimental colitis was induced in ceruloplasmin null (Cp(-/-)) and wild-type (WT) mice by dextran sulphate sodium administration. The role of ceruloplasmin was further evaluated by transplantation of WT macrophages into Cp(-/-) mice.
Results:
Cp(-/-) mice rapidly lost weight and were moribund by day 14, while WT mice survived at least 30 days. Colon culture supernatants from Cp(-/-) mice exhibited elevated levels of TNFα, KC and MCP-1, indicative of increased inflammation and neutrophil and macrophage infiltration. Elevated leucocytes and severe histopathology were observed in Cp(-/-) mice. Elevated protein carbonyl content was detected in colons from Cp(-/-) mice suggesting ceruloplasmin antioxidant activity might contribute to its protective function. Unexpectedly, intraperitoneal administration of human ceruloplasmin into Cp(-/-) mice did not afford protection. Bone marrow transplantation from WT mice or injection of isolated peripheral blood monocytes markedly reduced severity of colitis and morbidity in Cp(-/-) mice.
Conclusion:
Macrophage-derived ceruloplasmin contributes importantly to protection against inflammation and tissue injury in acute and chronic experimental colitis. The findings suggest that defects in ceruloplasmin expression or processing may influence the onset or progression of inflammatory bowel disease in patients.
Insights
Macrophage-derived ceruloplasmin is vital for protecting against colitis. Its absence worsens inflammation and tissue damage, suggesting a role in inflammatory bowel disease.
Area of Science:
- Gastroenterology
- Immunology
- Biochemistry
Background:
- Intestinal microflora and inflammatory cells are key in colitis pathogenesis.
- Ceruloplasmin (Cp) is an acute-phase protein with antioxidant and bactericidal properties.
Purpose of the Study:
- To investigate the role of ceruloplasmin in experimental colitis using a genetically modified mouse model.
Main Methods:
- Experimental colitis induced in ceruloplasmin null (Cp(-/-)) and wild-type (WT) mice using dextran sulfate sodium.
- Macrophage transplantation experiments were performed in Cp(-/-) mice.
Main Results:
- Cp(-/-) mice showed severe weight loss, morbidity, and increased inflammatory markers (TNFα, KC, MCP-1) compared to WT mice.
- Histopathology revealed elevated leukocytes and tissue damage in Cp(-/-) mice, suggesting Cp's protective, antioxidant role.
- Bone marrow or monocyte transplantation improved colitis outcomes in Cp(-/-) mice, highlighting macrophage-derived Cp's importance.
Conclusions:
- Macrophage-derived ceruloplasmin is crucial for protection against acute and chronic experimental colitis.
- Defects in ceruloplasmin may impact inflammatory bowel disease onset and progression in humans.
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