1. Complexes between C-Reactive Protein and Very Low Density Lipoprotein Delay Bacterial Clearance in Sepsis
- Author
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Julien Toh, Xiaoling Ge, Zhenxing Cheng, Weiping Yu, Simon T. Abrams, Colin Downey, Qian Yu, Cheng Hock Toh, Susan S Wang, and Guozheng Wang
- Subjects
Male ,Very low-density lipoprotein ,Kupffer Cells ,Phosphorylcholine ,Phagocytosis ,Immunology ,Bacteremia ,Plasma protein binding ,Lipoproteins, VLDL ,Microbiology ,Sepsis ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,medicine ,Animals ,Humans ,Immunology and Allergy ,Scavenger receptor ,Aged ,Phosphocholine ,biology ,Chemistry ,Receptors, IgG ,C-reactive protein ,U937 Cells ,Middle Aged ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,C-Reactive Protein ,Mutation ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,Protein Binding ,030215 immunology - Abstract
C-reactive protein (CRP) can increase up to 1000-fold in blood and form complexes with very low density lipoproteins (VLDL). These complexes are associated with worse outcomes for septic patients, and this suggests a potential pathological role in sepsis. Complex formation is heightened when CRP is over 200 mg/l and levels are associated with the severity of sepsis and blood bacterial culture positivity. Using a mouse bacteremia model, blood bacterial clearance can be delayed by i.v. injection of CRP–VLDL complexes. Complexes are more efficiently taken up by activated U937 cells in vitro and Kupffer cells in vivo than VLDL alone. Both in vitro–generated and naturally occurring CRP–VLDL complexes reduce phagocytosis of bacteria by activated U937 cells. Fcγ and scavenger receptors are involved and a competitive mechanism for clearance of CRP–VLDL complexes and bacteria is demonstrated. Interaction of phosphocholine groups on VLDL with CRP is the major driver for complex formation and phosphocholine can disrupt the complexes to reverse their inhibitory effects on phagocytosis and bacterial clearance. Increased formation of CRP–VLDL complexes is therefore harmful and could be a novel target for therapy in sepsis.
- Published
- 2020