title: Deletion of Crry and DAF on murine platelets stimulates thrombopoiesis and increases factor H-dependent resistance of peripheral platelets to complement attack.
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.
authors: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19401, USA.
authors: Lidia
authors: L
authors: Barata
authors: Takashi
authors: T
authors: Miwa
authors: Sayaka
authors: S
authors: Sato
authors: David
authors: D
authors: Kim
authors: Imran
authors: I
authors: Mohammed
authors: Wen-Chao
authors: WC
authors: Song
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018958:CD55 Antigens / Q000097:blood / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003176:Complement C3 / Q000096:biosynthesis / Q000172:deficiency; D017242:Complement Factor H / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008533:Megakaryocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011897:Random Allocation; D011951:Receptors, Complement / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D017463:Receptors, Complement 3b; D034061:Thrombopoiesis / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D018958:CD55 Antigens; C482970:CR1L protein, human; D003176:Complement C3; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D017242:Complement Factor H
references: Cell Mol Life Sci. 2002 Feb;59(2):220-9
references: 11915940
references: Blood. 2008 Aug 15;112(4):1109-19
references: 18524992
references: Science. 2000 Jan 21;287(5452):498-501
references: 10642554
references: Immunol Today. 1992 Jun;13(6):231-6
references: 1378280
references: J Immunol. 2006 Oct 15;177(8):5558-66
references: 17015743
references: Blood. 2008 Jan 15;111(2):732-40
references: 17916747
references: Blood. 2002 May 15;99(10):3707-16
references: 11986227
references: Physiol Genomics. 2008 Sep 17;35(1):1-4
references: 18612081
references: Blood. 2007 Feb 15;109(4):1503-6
references: 17032923
references: Blood. 2007 Jul 1;110(1):228-36
references: 17363730
references: Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):628-33
references: 9892684
references: Clin Immunol. 2006 Feb-Mar;118(2-3):127-36
references: 16338172
references: J Immunol. 2008 Aug 15;181(4):2732-40
references: 18684964
references: Mol Immunol. 2007 Jan;44(1-3):139-46
references: 16887189
references: J Am Soc Nephrol. 2013 Jan;24(1):53-65
references: 23204401
references: Mol Immunol. 2004 Jun;41(4):355-67
references: 15163532
references: Mol Immunol. 2009 Feb;46(5):803-11
references: 18947875
references: Blood. 2009 Mar 19;113(12):2684-94
references: 19136662
references: Int Immunopharmacol. 2001 Mar;1(3):445-59
references: 11367529
references: Clin Haematol. 1985 Feb;14(1):105-25
references: 3886232
references: Neonatology. 2010 Jun;98(1):100-8
references: 20134184
references: Mol Immunol. 2006 Mar;43(7):972-9
references: 16023208
references: Dev Biol. 2001 Feb 15;230(2):230-42
references: 11161575
references: Biochem J. 1998 Feb 15;330 ( Pt 1):163-8
references: 9461505
references: Cell Res. 2010 Jan;20(1):34-50
references: 20010915
references: Blood. 2002 Dec 15;100(13):4544-9
references: 12393518
references: N Engl J Med. 2001 Apr 5;344(14):1058-66
references: 11287977
references: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):240-5
references: 17182750
references: Nat Genet. 2002 Aug;31(4):424-8
references: 12091909
references: Immunogenetics. 1998 Nov-Dec;48(6):363-71
references: 9799332
references: Am J Transplant. 2012 Jun;12(6):1632-6
references: 22420623
references: Trends Immunol. 2008 Aug;29(8):380-7
references: 18602340
references: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2897-902
references: 21285368
references: Blood. 2008 Dec 15;112(13):4948-52
references: 18796626
references: J Am Soc Nephrol. 2007 Mar;18(3):811-22
references: 17229915
references: J Immunol. 2006 Nov 1;177(9):6308-16
references: 17056561
references: Gene. 1995 Sep 11;162(2):225-9
references: 7557433
references: J Immunol. 2006 Feb 1;176(3):1305-10
references: 16424154
references: Pediatr Res. 2004 Apr;55(4):581-4
references: 14739366