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Red Cell Biology & its Disorders
Interleukin-1 receptor inhibition reduces stroke size in a murine model of sickle cell disease
Jessica Venugopal,1 Jintao Wang,1 Jalal Mawri,2 Chiao Guo1 and Daniel T. Eitzman1
1University of Michigan Internal Medicine - Cardiology Division and 2University of Michigan, Ann Arbor, MI, USA
ABSTRACT
Sickle cell disease (SCD) is associated with chronic hemolytic anemia and a heightened inflammatory state. The causal role of inflamma- tory pathways in stroke associated with SCD is unclear. Therefore, the hypothesis that deletion of the non-hematopoietic interleukin-1 receptor (IL-1R) pool may be beneficial in SCD was pursued. Since potential deleterious effects of IL-1R signaling in SCD could be mediated via downstream production of interleukin-6 (IL-6), the role of the non- hematopoietic IL-6 pool was also addressed. Bone marrow transplanta- tion (BMT) from SCD to wild-type (WT) recipient mice was used to gen- erate SCD mice (Wt,SCDbmt). In order to generate mice with non- hematopoietic deficiency of IL-1R or IL-6, SCD marrow was transplant- ed into IL-1R deficient (IL1R-/-,SCDbmt) or IL-6 deficient recipients (IL6-/-, SCDbmt). Blood counts, reticulocytes, soluble E-selectin (sEsel), and IL-6 levels were analyzed 14-15 weeks post-BMT. Ischemic stroke was induced by middle cerebral artery (MCA) photothrombosis at 16 weeks post-BMT. A separate group of Wt,SCDbmt mice was given the IL-1R inhibitor, anakinra, following stroke induction. Seventy-two hours after MCA occlusion, stroke volume was assessed by staining brain sections with 2,3,5-triphenyltetrazolium chloride. Formalin-fixed brain sections were also stained for macrophages with MAC3, for endothelial activa- tion with ICAM-1, and for loss of blood brain barrier integrity with fib- rin(ogen) staining. All SCD mice generated by BMT were anemic and the severity of anemia was not different between Wt,SCDbmt, IL1R-/-,SCDbmt, and IL-6-/-,SCDbmt mice. Three days following MCA occlusion, stroke volume was significantly reduced in IL1R-/-,SCDbmt mice compared to Wt,SCDbmt mice and IL6-/-,SCDbmt mice. Plasma levels of sEsel were lower in IL1R-/-,SCDbmt compared to Wt,SCDbmt and IL-6-/-,SCDbmt mice. Post-stroke treatment of Wt,SCDbmt mice with anakinra decreased stroke size, leukocyte infiltration, ICAM-1 expres- sion, and fibrin(ogen) accumulation compared to vehicle-treated mice. Deficiency of non-hematopoietic IL-1R or treatment with an IL-1R antagonist is sufficient to confer protection against the increased stroke size associated with SCD. These effects of IL1R deficiency are associated with reduced endothelial activation, leukocyte infiltration, and blood brain barrier disruption, and are independent of non-hematopoietic IL-6 signaling.
Introduction
Sickle cell disease (SCD) is associated with acute and chronic vascular complica- tions leading to premature morbidity and mortality, including adverse cerebrovas- cular events, such as stroke.1 The stroke risk for a child with SCD is over 300 times greater than for a child without SCD2 with clinically apparent strokes occurring in 11% of SCD patients before the age of 20. Approximately two thirds of these patients experience recurrent cerebral infarction.3 Genotype greatly influences the
Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2469-2477
Correspondence:
DANIEL T. EITZMAN
deitzman@umich.edu
Received: March 10, 2020. Accepted: August 5, 2020. Pre-published: August 13, 2020.
https://doi.org/10.3324/haematol.2020.252395 ©2021 Ferrata Storti Foundation
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