Agonistic Anti-CD40 Antibody Triggers an Acute Liver Crisis With Systemic Inflammation in Humanized Sickle Cell Disease Mice
Dubach, Irina L
Swindle, Delaney C
Schaer, Dominik J
Buehler, Paul W
Irwin, David C
JournalFrontiers in Immunology
PublisherFrontiers Media S.A.
MetadataShow full item record
AbstractSickle cell disease (SCD) is an inherited hemolytic disorder, defined by a point mutation in the β-globin gene. Stress conditions such as infection, inflammation, dehydration, and hypoxia trigger erythrocyte sickling. Sickled red blood cells (RBCs) hemolyze more rapidly, show impaired deformability, and increased adhesive properties to the endothelium. In a proinflammatory, pro-coagulative environment with preexisting endothelial dysfunction, sickled RBCs promote vascular occlusion. Hepatobiliary involvement related to the sickling process, such as an acute sickle hepatic crisis, is observed in about 10% of acute sickle cell crisis incidents. In mice, ligation of CD40 with an agonistic antibody leads to a macrophage activation in the liver, triggering a sequence of systemic inflammation, endothelial cell activation, thrombosis, and focal ischemia. We found that anti-CD40 antibody injection in sickle cell mice induces a systemic inflammatory and hemodynamic response with accelerated hemolysis, extensive vaso-occlusion, and large ischemic infarctions in the liver mimicking an acute hepatic crisis. Administration of the tumor necrosis factor-α (TNF-α) blocker, etanercept, and the heme scavenger protein, hemopexin attenuated end-organ damage. These data collectively suggest that anti-CD40 administration offers a novel acute liver crisis model in humanized sickle mice, allowing for evaluation of therapeutic proof-of-concept.
Rights/TermsCopyright © 2021 Yalamanoglu, Dubach, Schulthess, Ingoglia, Swindle, Humar, Schaer, Buehler, Irwin and Vallelian.
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/15046
- The Red Blood Cell-Inflammation Vicious Circle in Sickle Cell Disease.
- Authors: Nader E, Romana M, Connes P
- Issue date: 2020
- Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease.
- Authors: Vinchi F, Costa da Silva M, Ingoglia G, Petrillo S, Brinkman N, Zuercher A, Cerwenka A, Tolosano E, Muckenthaler MU
- Issue date: 2016 Jan 28
- Hypoxia/reoxygenation stress increases markers of vaso-occlusive crisis in sickle SAD mice.
- Authors: Aufradet E, DeSouza G, Bourgeaux V, Bessaad A, Campion Y, Canet-Soulas E, Pialoux V, Chirico EN, Chevrier AM, Godfrin Y, Martin C
- Issue date: 2013 Jan 1
- A monocyte-TNF-endothelial activation axis in sickle transgenic mice: Therapeutic benefit from TNF blockade.
- Authors: Solovey A, Somani A, Belcher JD, Milbauer L, Vincent L, Pawlinski R, Nath KA, Kelm RJ Jr, Mackman N, O'Sullivan MG, Gupta K, Vercellotti GM, Hebbel RP
- Issue date: 2017 Nov
- Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin.
- Authors: Alishlash AS, Sapkota M, Ahmad I, Maclin K, Ahmed NA, Molyvdas A, Doran S, Albert CJ, Aggarwal S, Ford DA, Ambalavanan N, Jilling T, Matalon S
- Issue date: 2021 Aug