Sickle cell anemia: hepatic macrophages to the rescue

In this issue of Blood, Shi et al¹ demonstrate the importance of hepatic macrophages in the clearance of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13)-cleaved von Willebrand factor (VWF) in mice with sickle cell anemia (SCA). The authors discovered that the resulting short VWF fragments adhere to erythrocytes, and insufficient phagocytosis of these fragments fuels the aggressiveness of vaso-occlusive episodes associated with SCA.

Sickle cell disease is an inherited disorder due to a single mutation in the β-globin gene.² Yet, as the authors remind us, SCA “is a systemic disease with complex, incompletely elucidated pathologies.” For example, macrophage clearance of SCA erythrocytes is essential to prevent hemolysis and limit tissue damage and inflammatory processes caused by released heme.³ Macrophages are a diverse population, and Shi et al sought to identify the particular macrophage type(s) involved in the complex pathologic process(es) of SCA. Using single-cell RNA sequencing and fluorescence in situ transcriptome techniques, the authors identified a significant presence of hepatic macrophages within the vessel wall, particularly in SCA mouse liver compared with normal mouse liver. Several macrophage populations, including Kupffer-cell receptor marker (C-type lectin receptor, Clec4f) and a few macrophage scavenger receptors (Macro) were shown to have enhanced erythrophagocytosis and macrophage phagocytosis activity, thus reducing tissue damage in the SCA mouse liver.

VWF promotes vaso-occlusive events (VOEs) and thromboinflammation in SCA.^4,5 VWF is elevated in individuals with SCA, and its clearance by macrophages is obviously important.⁶ The authors found that the Clef4fMacro macrophage subset was most active in VWF clearance. Removal of VWF by these macrophages is preceded by ADAMTS13 proteolytic cleavage of VWF; the importance of this process is highlighted by the fact that administering recombinant ADAMTS13 alleviates VOEs,⁷ and dysregulation of the VWF–ADAMTS13 axis promotes SCA pathogenesis.⁸ Further, cleavage requires desialylation of VWF in the liver, thereby supporting the role of sialyation by hepatic macrophages in this process.

Cleaved VWF assembles into higher- and lower-molecular-weight multimers.⁹ In their study, Shi et al identified a new pathologic activity of the lower-molecular-weight VWF. The lower-molecular-weight fragments bind to sickle erythrocytes and exacerbate VOEs if these fragments are not cleared from the circulation. Ac2-26, a peptide derived from Annexin A1, stimulates the phagocytosis activity of bone marrow macrophages. Shi et al showed that Ac2-26 increased colocalization of VWF with macrophages and reduced vaso-occlusion, a finding that suggests a “new therapeutic option for the treatment of VOE.”

In conclusion, targeting macrophages as innovative therapeutic approaches for SCA may pave the way to further our knowledge of the complexity of this disease.

Conflict-of-interest disclosure: The authors declare no competing financial interests.