N-glycosylation deficiency reduces ICAM-1 induction and impairs inflammatory response.
Congenital disorders of glycosylation (CDGs) result from mutations in various N-glycosylation genes. The most common type, phosphomannomutase-2 (PMM2)-CDG (CDG-Ia), is due to deficient PMM2 (Man-6-P → Man-1-P). Many patients die from recurrent infections, but the mechanism is unknown. We found that glycosylation-deficient patient fibroblasts have less intercellular adhesion molecule-1 (ICAM-1), and because of its role in innate immune response, we hypothesized that its reduction might help explain recurrent infections in CDG patients. We, therefore, studied mice with mutations in Mpi encoding phosphomannose isomerase (Fru-6-P → Man-6-P), the cause of human MPI-CDG. We challenged MPI-deficient mice with an intraperitoneal injection of zymosan to induce an inflammatory response and found decreased neutrophil extravasation compared with control mice. Immunohistochemistry of mesenteries showed attenuated neutrophil egress, presumably due to poor ICAM-1 response to acute peritonitis. Since phosphomannose isomerase (MPI)-CDG patients and their cells improve glycosylation when given mannose, we provided MPI-deficient mice with mannose-supplemented water for 7 days. This restored ICAM-1 expression on mesenteric endothelial cells and enhanced transendothelial migration of neutrophils during acute inflammation. Attenuated inflammatory response in glycosylation-deficient mice may result from a failure to increase ICAM-1 on the vascular endothelial surface and may help explain recurrent infections in patients.
Genetic Disease Program, Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
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D000818:Animals; D002478:Cells, Cultured; D018981:Congenital Disorders of Glycosylation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019587:Dietary Supplements; D006031:Glycosylation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*; D008358:Mannose / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism; D008359:Mannose-6-Phosphate Isomerase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015054:Zymosan / Q000008:administration & dosage
D018799:Intercellular Adhesion Molecule-1; D015054:Zymosan; D008359:Mannose-6-Phosphate Isomerase; D008358:Mannose
CDG; ICAM-1; inflammatory response; mannose supplementation