CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso‐occlusion during hemolytic transfusion reactions

Abstract

Hemolytic transfusion reactions (HTR) can produce acute vaso-occlusive crisis (VOC), a major cause of morbidity and mortality in sickle cell disease (SCD) patients; however, the mechanisms remain unknown. We established a model of alloimmune IgG-mediated HTR using a well-characterized humanized murine model of SCD. In this model, HTR induced acute VOC, resulting in shortened survival of the SCD mice (by 3 h, P<0.05, log-rank test). Acute VOC was associated with elevated circulating inflammatory chemokine levels, including the neutrophil chemoattractant CXCL1, which was strikingly elevated (139 ± 35 vs 43 ± 10 pg/ml, P<0.05). Recombinant CXCL1 administration corresponding to the HTR-elicited endogenous CXCL1 levels induced acute VOC in non-transfused SCD mice, characterized by leukocyte recruitment in venules (2571 ± 193 vs 1464 ± 194 adherent leukocytes per mm2, P<0.01), marked interactions with circulating red blood cells, reduced venular flow rates (430 ± 34 vs 310 ± 36 nL/s, P<0.05), and shortened survival (by 4 h, P<0.001, log-rank test). In contrast, blocking its receptor, CXCR2, prevented HTR-elicited acute VOC and prolonged the survival of SCD mice (by 6 h, P<0.01, log-rank test). Thus, CXCL1 is a key inflammatory mediator of acute VOC in SCD mice and targeted inhibition of CXCL1 and/or CXCR2 may provide new approaches for treating acute VOC in SCD patients.