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Intercellular adhesion molecule‐1 deficiency correlates with impaired inflammatory response in congenital disorder of glycosylation (607.2)
Author(s) -
He Ping,
Freeze Hudson
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.607.2
Subject(s) - tunicamycin , inflammation , glycosylation , intercellular adhesion molecule 1 , immunology , zymosan , innate immune system , neutrophil elastase , mesenteries , medicine , biology , immune system , microbiology and biotechnology , biochemistry , unfolded protein response , endoplasmic reticulum , in vitro , anatomy
Congenital Disorders of Glycosylation (CDGs) result from mutations in various N‐glycosylation genes. Many patients are prone to infections, but the mechanism is unknown. We found that CDG patient fibroblasts have less intercellular adhesion molecule‐1 (ICAM‐1), and because of its role in innate immune response, we hypothesized that its reduction may explain recurrent infections. In support of this, tunicamycin blocks TNF‐α induced ICAM‐1 production, suggesting that many CDG cells may show poor ICAM‐1 response. We, therefore, investigated a mouse model of MPI‐CDG, deficient in phosphomannose isomerase. We challenged MPI‐deficient mice with an intraperitoneal injection of pro‐inflammatory mediator (Zymosan) and found decreased neutrophil extravasation. Immunohistochemical staining of mesenteries showed attenuated neutrophil egress, presumably due to poor ICAM‐1 response to acute peritonitis. Since MPI‐CDG patients and their cells improve glycosylation when given mannose, we provided MPI‐deficient mice with mannose‐supplemented water for 7 days. This increased ICAM‐1 expression on mesenteric endothelial cells of Zymosan‐challenged mice and enhanced neutrophils exudation compared to untreated controls. Attenuated inflammatory response in glycosylation‐deficient mice may result from ICAM‐1 deficiency on the vascular endothelial surface and may help explain high mortality in patients. Grant Funding Source : supported by the Rocket Fund & NIH R01 DK55615