Blocking CD47 restores efferocytosis—a phagocytic process that removes dead or dying cells—and shows promise as novel therapeutic approach for treating antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), according to a new study published in JCI Insight.
“Targeting CD47 is now in the spotlight as a therapy for various diseases involving impaired efferocytosis. Here, blockade of CD47 restored the efferocytosis of NETs [neutrophil extracellular traps] and necrotic endothelium in an ex vivo model and protected against renal injury in AAV mice,” the researchers said.
Immunostaining analysis of human renal tissues revealed high expression of CD47 in crescentic glomerular lesions of patients with AAV compared with patients with lupus nephritis or minor glomerular abnormalities.
In ex vivo studies, ANCA-induced netting neutrophils were found to increase CD47 expression, leading to reduced efferocytosis. The increased CD47 expression was observed on the cell membrane of neutrophils with ANCA- and phorbol myristate acetate-induced NETs, but not on extracellular DNA fibers.
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Mechanistically, the researchers showed that ANCA-induced NETs evade efferocytosis by upregulating CD47.
The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice, which develop systemic necrotizing glomerulonephritis with ANCA production, led to the restoration of efferocytosis. Moreover, it effectively reduced NET formation and myeloperoxidase-ANCA titers, downregulated proinflammatory genes, such as Ifna, Ifng, Mcp1, Prf1, and Il1b, and improved renal disease in AAV.
Additional experiments aimed at investigating the impact of CD47 blockade on immune cell dynamics in the kidneys of SCG/Kj mice suggested that activated macrophages involved in efferocytosis may facilitate the recruitment of immune cells beyond what is necessary for focal cellular waste disposal.
CD47 is a cell surface protein that functions as a “don’t eat me” signal or a “marker of self.”
Reference
Shiratori-Aso S, Nakazawa D, Kudo T, et al. CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps. JCI Insight. Published online June 27, 2023. doi:10.1172/jci.insight.167486
