Severity of Transfusion-Related Acute Lung Injury in mice expressing human FcgRIIA is determined by platelet-released serotonin

Objective Transfusion-related acute lung injury (TRALI) remains a major cause of transfusion-related fatalities. TRALI can occur after transfusion of blood products containing allogeneic antibodies targeting cells of the recipient. The involvement of the human Fcg receptors in this type of TRALI has been poorly assessed. FcgRIIA/CD32A is an activating low affinity receptor for immunoglobulin G (IgG) expressed on human platelets and immune cells, whereas no corresponding ortholog is present in mice. Therefore, since the current murine models incompletely recapitulate the human immunology, our understanding of the pathogenesis of antibody-mediated TRALI is partial. Our study aimed at evaluating the contribution of FcgRIIA/CD32A in a model of antibody-mediated TRALI in transgenic mice expressing this human receptor.

Material and Methods Antibody‐mediated TRALI was induced in control mice (WT) and mice transgenic for human CD32A (CD32A+) by lipopolysaccharide priming followed by administration of a recombinant chimeric human/mouse anti-MHC I monoclonal antibody (derived from clone 34-1-2S).

Results TRALI responses were more severe in CD32A+ than in WT mice in terms of pulmonary edema and mortality, the latter reaching 90% in CD32A+ versus 40% in WT animals within 2-hours. Unlike in WT mice, monocytes/macrophages were only accessory for the initiation of TRALI in CD32A+ mice, pointing to the decisive contribution of another cell type. Soon after induction of TRALI, platelet counts dropped more dramatically in CD32A+ than in WT mice. Moreover, massive release of platelet granule contents was observed only in the peripheral blood of CD32A+ animals. Platelet depletion prevented the exacerbation of TRALI observed in CD32A+ mice but did not affect TRALI in the WT. Long-term treatment with the selective serotonin reuptake inhibitor fluoxetine, to deplete the serotonin content of platelet granules, selectively abolished the aggravation of lung edema in CD32A+ mice. This effect could also be achieved by blockade of the 5-hydroxytryptamine 2A serotonin receptor with sarpogrelate when the drug was administered before or after the induction of TRALI.

Conclusion Our findings identify platelet FcgRIIA/CD32A as a critical determinant of the severity of TRALI and provide a rationale for designing prophylactic and therapeutic strategies targeting the serotonin pathway to attenuate antibody-mediated TRALI in patients.

Publication History

Article published online:
18 June 2021