Advertisement

Elimination of the fibrinogen integrin αMβ2-binding motif improves renal pathology in mice with sickle cell anemia

Md Nasimuzzaman, Paritha I. Arumugam, Eric S. Mullins, Jeanne M. James, Katherine VandenHeuvel, Marilou G. Narciso, Maureen A. Shaw, Sarah McGraw, Bruce J. Aronow and Punam Malik

Key Points

  • Elimination of the fibrinogen integrin αMβ2-binding motif improves renal pathology in SCA.

  • The fibrinogen γ390-396 motif represents a novel therapeutic target that may improve sickle cell disease outcomes.

Abstract

Sickle cell anemia (SCA) is caused by a point mutation in the β-globin gene that leads to devastating downstream consequences including chronic hemolytic anemia, episodic vascular occlusion, and cumulative organ damage resulting in death. SCA patients show coagulation activation and inflammation even in the absence of vascular occlusion. The coagulation factor fibrinogen is not only central to hemostasis but also plays important roles in pathologic inflammatory processes, in part by engaging neutrophils/macrophages through the αMβ2 integrin receptor. To determine whether fibrin(ogen)-mediated inflammation is a driver of SCA-associated pathologies, hematopoietic stem cells from Berkeley sickle mice were transplanted into homozygous Fibγ390-396A mice that express normal levels of a mutant form of fibrin(ogen) that does not engage αMβ2. Fibγ390-396A mice with SCA displayed an impressive reduction of reactive oxygen species (ROS) in white blood cells (WBCs), decreased circulating inflammatory cytokines/chemokines, and significantly improved SCA-associated glomerular pathology highlighted by reduced glomerulosclerosis, inflammatory cell infiltration, ischemic lesions, mesangial thickening, mesangial hypercellularity, and glomerular enlargement. In addition, Fibγ390-396A mice with SCA had improved glomerular protective responses and podocyte/mesangial transcriptional signatures that resulted in reduced albuminuria. Interestingly, the fibrinogen γ390-396A mutation had a negligible effect on cardiac, lung, and liver functions and pathologies in the context of SCA over a year-long observation period. Taken together, our data support that fibrinogen significantly contributes to WBC-driven inflammation and ROS production, which is a key driver of SCA-associated glomerulopathy, and may represent a novel therapeutic target against irreversible kidney damage in SCA.

  • Submitted January 26, 2019.
  • Accepted April 12, 2019.
View Full Text