Leishmania Infection-Induced Proteolytic Processing of SIRPa in Macrophages

The shedding of cell surface receptors may bring synergistic outcomes through the loss of receptor-mediated cell signaling and competitive binding of the shed soluble receptor to its ligand. Thus, soluble receptors have both biological importance and diagnostic importance as biomarkers in immunological disorders. Signal regulatory protein a (SIRPa), one of the receptors responsible for the 'don't-eat-me' signal, is expressed by myeloid cells where its expression and function are in part regulated by proteolytic cleavage. However, reports on soluble SIRPa as a biomarker are limited. We previously reported that mice with experimental visceral leishmaniasis (VL) manifest anemia and enhanced hemophagocytosis in the spleen accompanied with decreased SIRPa expression. Here, we report increased serum levels of soluble SIRPa in mice infected with Leishmania donovani, a causative agent of VL. Increased soluble SIRPa was also detected in a culture supernatant of macrophages infected with L. donovani in vitro, suggesting the parasite infection promotes ectodomain shedding of SIRPa on macrophages. The release of soluble SIRPa was partially inhibited by an ADAM proteinase inhibitor in both LPS stimulation and L. donovani infection, suggesting a shared mechanism for cleavage of SIRPa in both cases. In addition to the ectodomain shedding of SIRPa, both LPS stimulation and L. donovani infection induced the loss of the cytoplasmic region of SIRPa. Although the effects of these proteolytic processes or changes in SIRPa still remain unclear, these proteolytic regulations on SIRPa during L. donovani infection may explain hemophagocytosis and anemia induced by infection, and serum soluble SIRPa may serve as a biomarker for hemophagocytosis and anemia in VL and the other inflammatory disorders.

Automated summary

The shedding of cell surface receptors can have synergistic outcomes by disrupting cell signaling and binding with ligands. Soluble receptors, such as SIRPa, have biological and diagnostic importance in immunological disorders. In this study, increased levels of soluble SIRPa were observed in mice infected with Leishmania donovani, suggesting its potential role as a biomarker for disorders like hemophagocytosis and anemia.