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.
© 2018 Wiley Periodicals, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Anemia, Sickle Cell / drug therapy
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Anemia, Sickle Cell / genetics
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Anemia, Sickle Cell / immunology*
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Anemia, Sickle Cell / pathology
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Animals
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Antibodies, Neutralizing / pharmacology*
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Cerebrovascular Disorders / drug therapy
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Cerebrovascular Disorders / genetics
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Cerebrovascular Disorders / immunology*
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Cerebrovascular Disorders / pathology
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Complement C3 / genetics
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Complement C3 / immunology*
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Complement C5a / antagonists & inhibitors
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Complement C5a / genetics
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Complement C5a / immunology*
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Complement Membrane Attack Complex / genetics
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Complement Membrane Attack Complex / immunology
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Disease Models, Animal
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E-Selectin / genetics
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E-Selectin / immunology
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Gene Expression Regulation
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Humans
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Immunity, Innate
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / immunology
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Kidney / blood supply
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Kidney / drug effects
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Kidney / immunology
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Kidney / pathology
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Liver / blood supply
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Liver / drug effects
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Liver / immunology
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Liver / pathology
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Lung / blood supply
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Lung / drug effects
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Lung / immunology
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Lung / pathology
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Male
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Mice
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Mice, Transgenic
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NF-kappa B / genetics
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NF-kappa B / immunology
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P-Selectin / antagonists & inhibitors
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P-Selectin / genetics
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P-Selectin / immunology
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Receptor, Anaphylatoxin C5a / antagonists & inhibitors
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Receptor, Anaphylatoxin C5a / genetics
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Receptor, Anaphylatoxin C5a / immunology*
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Signal Transduction
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Vascular Cell Adhesion Molecule-1 / genetics
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Vascular Cell Adhesion Molecule-1 / immunology
Substances
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Antibodies, Neutralizing
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Complement C3
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Complement Membrane Attack Complex
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E-Selectin
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Icam1 protein, mouse
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NF-kappa B
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P-Selectin
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Receptor, Anaphylatoxin C5a
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SC5b-9 protein complex
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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Complement C5a