Deletion of Crry and DAF on Murine Platelets Stimulates Thrombopoiesis and Increases Factor H-Dependent Resistance of Peripheral Platelets to Complement Attack

Barata, L.; Miwa, T.; Sato, S.; Kim, D.; Mohammed, I.; Song, W.-C.

Abstract

Complement receptor 1-related gene/protein y (Crry) and decay-accelerating factor (DAF) are two murine membrane C3 complement regulators with overlapping functions. Crry deletion is embryonically lethal whereas DAF-deficient mice are generally healthy. Crry(-/-)DAF(-/-) mice were viable on a C3(-/-) background, but platelets from such mice were rapidly destroyed when transfused into C3-sufficient mice. In this study, we used the cre-lox system to delete platelet Crry in DAF(-/-) mice and studied Crry/DAF-deficient platelet development in vivo. Rather than displaying thrombocytopenia, Pf4-Cre(+)-Crry(flox/flox) mice had normal platelet counts and their peripheral platelets were resistant to complement attack. However, chimera mice generated with Pf4-Cre(+)-Crry(flox/flox) bone marrows showed platelets from C3(-/-) but not C3(+/+) recipients to be sensitive to complement activation, suggesting that circulating platelets in Pf4-Cre(+)-Crry(flox/flox) mice were naturally selected in a complement-sufficient environment. Notably, Pf4-Cre(+)-Crry(flox/flox) mouse platelets became complement susceptible when factor H function was blocked. Examination of Pf4-Cre(+)-Crry(flox/flox) mouse bone marrows revealed exceedingly active thrombopoiesis. Thus, under in vivo conditions, Crry/DAF deficiency on platelets led to abnormal platelet turnover, but peripheral platelet count was compensated for by increased thrombopoiesis. Selective survival of Crry/DAF-deficient platelets aided by factor H protection and compensatory thrombopoiesis demonstrates the cooperation between membrane and fluid phase complement inhibitors and the body's ability to adaptively respond to complement regulator deficiencies.

Citation

Barata, L., Miwa, T., Sato, S., Kim, D., Mohammed, I., & Song, W.-C. (2013). Deletion of Crry and DAF on Murine Platelets Stimulates Thrombopoiesis and Increases Factor H-Dependent Resistance of Peripheral Platelets to Complement Attack. Journal of Immunology, 190(6), 2886-2895. https://doi.org/10.4049/jimmunol.1202536

• Journal Article Type: Article
• Acceptance Date: Jan 8, 2013
• Online Publication Date: Feb 6, 2013
• Publication Date: Mar 15, 2013
• Deposit Date: Nov 16, 2018
• Journal: Journal of Immunology
• Print ISSN: 0022-1767
• Electronic ISSN: 1550-6606
• Publisher: American Association of Immunologists
• Peer Reviewed: Peer Reviewed
• Volume: 190
• Issue: 6
• Pages: 2886-2895
• DOI: https://doi.org/10.4049/jimmunol.1202536
• Public URL: https://nottingham-repository.worktribe.com/output/1277050