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Abstract SIRPα is an inhibitory receptor with the canonical ligand CD47. Here, we show that human serine protease inhibitor A3 (SERPINA3) and its mouse ortholog SERPINA3k function as soluble binders and activators of SIRPα, suppressing SIRPα+ macrophages, neutrophils, dendritic cells and natural killer cells. SERPINA3(k) treatment alleviates lipopolysaccharide-induced pneumonia and ameliorates experimental autoimmune encephalomyelitis and rheumatoid arthritis.
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