Critical role of C5a in sickle cell disease

Gregory M Vercellotti, Agustin P Dalmasso, Terry R. Schaid, Julia Nguyen, Chunsheng Chen, Marna E Ericson, Fuad Abdulla, Trevor Killeen, Margaret A. Lindorfer, Ronald P. Taylor, John D Belcher

Research output: Contribution to journalArticle

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Abstract

Innate immune complement activation may contribute to sickle cell disease (SCD) pathogenesis. Ischemia-reperfusion physiology is a key component of the inflammatory and vaso-occlusive milieu in SCD and is associated with complement activation. C5a is an anaphylatoxin, a potent pro-inflammatory mediator that can activate leukocytes, platelets, and endothelial cells, all of which play a role in vaso-occlusion. We hypothesize that hypoxia-reoxygenation (H/R) in SCD mice activates complement, promoting inflammation and vaso-occlusion. At baseline and after H/R, sickle Townes-SS mice had increased C3 activation fragments and C5b-9 deposition in kidneys, livers and lungs and alternative pathway Bb fragments in plasma compared to control AA-mice. Activated complement promoted vaso-occlusion (microvascular stasis) in SS-mice; infusion of zymosan-activated, but not heat-inactivated serum, induced substantial vaso-occlusion in the skin venules of SS-mice. Infusion of recombinant C5a induced stasis in SS, but not AA-mice that was blocked by anti-C5a receptor (C5aR) IgG. C5a-mediated stasis was accompanied by inflammatory responses in SS-mice including NF-κB activation and increased expression of TLR4 and adhesion molecules VCAM-1, ICAM-1, and E-selectin in the liver. Anti-C5aR IgG blocked these inflammatory responses. Also, C5a rapidly up-regulated Weibel-Palade body P-selectin and von Willebrand factor on the surface of human umbilical vein endothelial cells in vitro and on vascular endothelium in vivo. In SS-mice, a blocking antibody to P-selectin inhibited C5a-induced stasis. Similarly, an antibody to C5 that blocks murine C5 cleavage or an antibody that blocks C5aR inhibited H/R-induced stasis in SS-mice. These results suggest that inhibition of C5a may be beneficial in SCD.

Original languageEnglish (US)
Pages (from-to)327-337
Number of pages11
JournalAmerican Journal of Hematology
Volume94
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Sickle Cell Anemia
Anaphylatoxin C5a Receptor
P-Selectin
Complement Activation
Immunoglobulin G
Weibel-Palade Bodies
Anaphylatoxins
Complement Membrane Attack Complex
Blocking Antibodies
E-Selectin
Zymosan
Venules
Vascular Cell Adhesion Molecule-1
Antibodies
Liver
Human Umbilical Vein Endothelial Cells
Vascular Endothelium
von Willebrand Factor
Intercellular Adhesion Molecule-1
Reperfusion

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Critical role of C5a in sickle cell disease. / Vercellotti, Gregory M; Dalmasso, Agustin P; Schaid, Terry R.; Nguyen, Julia; Chen, Chunsheng; Ericson, Marna E; Abdulla, Fuad; Killeen, Trevor; Lindorfer, Margaret A.; Taylor, Ronald P.; Belcher, John D.

In: American Journal of Hematology, Vol. 94, No. 3, 01.03.2019, p. 327-337.

Research output: Contribution to journalArticle

Vercellotti, GM, Dalmasso, AP, Schaid, TR, Nguyen, J, Chen, C, Ericson, ME, Abdulla, F, Killeen, T, Lindorfer, MA, Taylor, RP & Belcher, JD 2019, 'Critical role of C5a in sickle cell disease', American Journal of Hematology, vol. 94, no. 3, pp. 327-337. https://doi.org/10.1002/ajh.25384
Vercellotti, Gregory M ; Dalmasso, Agustin P ; Schaid, Terry R. ; Nguyen, Julia ; Chen, Chunsheng ; Ericson, Marna E ; Abdulla, Fuad ; Killeen, Trevor ; Lindorfer, Margaret A. ; Taylor, Ronald P. ; Belcher, John D. / Critical role of C5a in sickle cell disease. In: American Journal of Hematology. 2019 ; Vol. 94, No. 3. pp. 327-337.
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AU - Abdulla, Fuad

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